64 results on '"Giralt, Sergio"'
Search Results
2. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses.
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Ailawadhi S, Arnulf B, Patel KK, Cavo M, Nooka AK, Manier S, Callander NS, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Abrahamsen IW, Baz RC, Broijl A, Chen C, Jagannath S, Raje N, Scheid C, Delforge M, Benjamin R, Pabst T, Iida S, Berdeja JG, Giralt SA, Truppel-Hartmann A, Chen Y, Zhong X, Wu F, Piasecki J, Eliason L, Dhanda DS, Felten J, Caia A, Cook M, Popa-Mckiver M, and Rodriguez-Otero P
- Abstract
Outcomes are poor in triple-class-exposed (TCE) relapsed/refractory multiple myeloma (RRMM). In the phase 3 KarMMa-3 (clinicaltrials.gov; NCT03651128) trial, patients with TCE RRMM and 2-4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary endpoint; 13.3 vs 4.4 months; P<.0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median (95% CI) was 41.4 (30.9-not reached [NR]) vs 37.9 (23.4-NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE RRMM. NCT03651128., (Copyright © 2024 American Society of Hematology.)
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- 2024
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3. Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma.
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Firestone RS, Socci ND, Shekarkhand T, Zhu M, Qin WG, Hultcrantz M, Mailankody S, Tan CR, Korde N, Lesokhin AM, Hassoun H, Shah U, Maclachlan KH, Rajeeve S, Landau HJ, Scordo M, Shah GL, Lahoud OB, Giralt S, Murata K, Usmani SZ, and Chung DJ
- Subjects
- Humans, Male, Female, Middle Aged, Antibodies, Bispecific therapeutic use, Aged, Antibodies, Monoclonal, Humanized, Multiple Myeloma immunology, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Multiple Myeloma pathology, Multiple Myeloma therapy, B-Cell Maturation Antigen genetics, B-Cell Maturation Antigen immunology, Drug Resistance, Neoplasm
- Abstract
Abstract: B-cell maturation antigen (BCMA)-targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 × BCMA bispecific antibody, 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy-naïve patients. Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and 1 of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from 1 patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen., (© 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.)
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- 2024
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4. Optimizing high dose melphalan.
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Shah G, Giralt S, and Dahi P
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- Humans, Melphalan adverse effects, Busulfan therapeutic use, Bendamustine Hydrochloride therapeutic use, Transplantation, Autologous, Transplantation Conditioning adverse effects, Multiple Myeloma drug therapy, Multiple Myeloma etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Melphalan, has been a major component of myeloma therapy since the 1950s. In the context of hematopoietic cell transplantation (HCT), high dose melphalan (HDM) is the most common conditioning regimen used due to its potent anti-myeloma effects and manageable toxicities. Common toxicities associated with HDM include myelosuppression, gastrointestinal issues, and mucositis. Established approaches to reduce these toxicities encompass dose modification, nausea prophylaxis with 5HT3 receptor antagonists, cryotherapy, amifostine use, and growth factors. Optimization of melphalan exposure through personalized dosing and its combination with other agents like busulfan, or bendamustine show promise. Propylene glycol-free melphalan (Evomela) represents a novel formulation aiming to enhance drug stability and reduce adverse effects. This review explores strategies to enhance the efficacy and mitigate the toxicity of HDM in multiple myeloma. Future directions involve exploring these strategies in clinical trials to improve the safety and efficacy of HDM, thereby enhancing outcomes for multiple myeloma patients undergoing autologous HCT., Competing Interests: Declaration of Competing Interest None relevant to this topic., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2024
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5. Recommendations for Management of Secondary Antibody Deficiency in Multiple Myeloma.
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Giralt S, Jolles S, Kerre T, Lazarus HM, Mustafa SS, Papanicolaou GA, Ria R, Vinh DC, and Wingard JR
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- Humans, Immunization, Passive, Antibodies therapeutic use, Multiple Myeloma complications, Multiple Myeloma diagnosis, Multiple Myeloma therapy, Agammaglobulinemia therapy, Immunologic Deficiency Syndromes drug therapy
- Abstract
Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes., Competing Interests: Disclosure SJ has received support for conferences, speaker, advisory boards, trials, data and safety monitoring boards, and projects with CSL Behring, Takeda, Swedish Orphan Biovitrum, Biotest, Binding Site, Grifols, BPL, Octapharma, LFB, Pharming, GSK, Weatherden, Zarodex, Sanofi, and UCB Pharma. SG has received research funding from Miltenyi Biotec, Takeda, Celgene, Amgen, Sanofi, Johnson and Johnson, and Actinium and is on the advisory boards for: Kite Pharmaceuticals, Celgene, Sanofi, Novartis, Johnson and Johnson, Amgen, Takeda, Jazz Pharmaceuticals, Actinium Pharmaceuticals and CSL Behring. TK has received support (never on a personal account) for conferences, speaker bureaus, advisory boards, trials, data and safety monitoring boards, and projects with Sanofi, Takeda, BMS, Johnson & Johnson, MSD, Novartis, Gilead, Octapharma and CSL Behring. HML has received consultancy fees and support for advisory boards from CSL Behring and Actinium Pharmaceuticals; is a member of the data safety and monitoring boards for BMS, BioSight, and Celgene; is a consultant, promotional speaker, and a member of the advisory boards for Jazz Pharmaceuticals and Seattle Genetics; is a promotional speaker for AstraZeneca; has received consultancy fees and has stock options with Partner Therapeutics; and has received consultancy fees from Pluristem. SM has received support for an advisory board and speaker bureaus with CSL Behring. GAP has received grants from Merck and Takeda and received support for advisory boards, data and safety monitoring boards, consultancy, speaker projects with Symbio, Merck, MSD, Allovir, Vera, Amplyx, Pfizer, Takeda, Cidara, Octapharma, Astellas and CSL Behring. RR has received support for advisory boards, data and safety monitoring boards, and speaker bureaus with Janssen Cilag, BMS, Celgene, Takeda, CSL Behring and Octapharma. DCV has received salary support from Fonds de Recherche du Québec - Santé Senior Clinician-Scientist scholar program; clinical trial support from CSL Behring, Cidara Therapeutics, Moderna, and Janssen; has received honoraria for advisory board consultations or speaker presentations from Astra Zeneca, GSK, Merck Canada, CSL Behring, Moderna, Novartis Canada, and UCB Biosciences GmbH; and has a patent application pending (Electronic Filing System ID: 40101099) and a report of invention submitted to McGill University (Track code: D2021-0043). JRW has received support for advisory boards and data and safety monitoring boards from CSL Behring, Cidara, Merck, Celgene, Ansun, and Takeda and royalties from UptoDate., (Copyright © 2023. Published by Elsevier Inc.)
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- 2023
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6. A phase 2 study of interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract.
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Ponce DM, Alousi AM, Nakamura R, Slingerland J, Calafiore M, Sandhu KS, Barker JN, Devlin S, Shia J, Giralt S, Perales MA, Moore G, Fatmi S, Soto C, Gomes A, Giardina P, Marcello L, Yan X, Tang T, Dreyer K, Chen J, Daley WL, Peled JU, van den Brink MRM, and Hanash AM
- Subjects
- Humans, Lower Gastrointestinal Tract, Adrenal Cortex Hormones therapeutic use, Interleukin-22, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease drug therapy, Graft vs Host Disease etiology
- Abstract
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This trial was registered at www.clinicaltrials.gov as NCT02406651., (© 2023 by The American Society of Hematology.)
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- 2023
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7. Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy.
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Van Oekelen O, Nath K, Mouhieddine TH, Farzana T, Aleman A, Melnekoff DT, Ghodke-Puranik Y, Shah GL, Lesokhin A, Giralt S, Thibaud S, Rossi A, Rodriguez C, Sanchez L, Richter J, Richard S, Cho HJ, Chari A, Usmani SZ, Jagannath S, Shah UA, Mailankody S, and Parekh S
- Subjects
- Humans, Salvage Therapy, B-Cell Maturation Antigen, Neoplasm Recurrence, Local, Immunotherapy, Adoptive, Multiple Myeloma drug therapy, Receptors, Chimeric Antigen
- Abstract
B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration-approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post-CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval [CI], 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell-engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell-engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell-engaging therapies appear to maintain pronounced clinical activity in this setting., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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8. Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant.
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Miltiadous O, Waters NR, Andrlová H, Dai A, Nguyen CL, Burgos da Silva M, Lindner S, Slingerland J, Giardina P, Clurman A, Armijo GK, Gomes ALC, Lakkaraja M, Maslak P, Scordo M, Shouval R, Staffas A, O'Reilly R, Taur Y, Prockop S, Boelens JJ, Giralt S, Perales MA, Devlin SM, Peled JU, Markey KA, and van den Brink MRM
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- CD4-Positive T-Lymphocytes, Humans, Lymphocyte Count, RNA, Ribosomal, 16S, Transplantation, Homologous, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation
- Abstract
Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation., (© 2022 by The American Society of Hematology.)
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- 2022
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9. Getting blood out of a stone: Identification and management of patients with poor hematopoietic cell mobilization.
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Chen J, Lazarus HM, Dahi PB, Avecilla S, and Giralt SA
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- Humans, Risk Factors, Benzylamines therapeutic use, Cyclams therapeutic use, Granulocyte Colony-Stimulating Factor therapeutic use, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cells, Stem Cell Niche drug effects
- Abstract
Hematopoietic cell transplantation (HCT) has become a primary treatment for many cancers. Nowadays, the primary source of hematopoietic cells is by leukapheresis collection of these cells from peripheral blood, after a forced egress of hematopoietic cells from marrow into blood circulation, a process known as "mobilization". In this process, mobilizing agents disrupt binding interactions between hematopoietic cells and marrow microenvironment to facilitate collection. As the first essential step of HCT, poor mobilization, i.e. failure to obtain a desired or required number of hematopoietic cell, is one of the major factors affecting engraftment or even precluding transplantation. This review summarizes the available mobilization regimens using granulocyte-colony stimulating factor (G-CSF) and plerixafor, as well as the current understanding of the factors that are associated with poor mobilization. Strategies to mobilize patients or healthy donors who failed previous mobilization are discussed. Multiple novel agents are under investigation and some of them have shown the potential to enhance the mobilization response to G-CSF and/or plerixafor. Further investigation of the risk factors including genetic factors will offer an opportunity to better understand the molecular mechanism of mobilization and help develop new therapeutic strategies for successful mobilizations., (Copyright © 2020. Published by Elsevier Ltd.)
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- 2021
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10. Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study.
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Khan N, Lindner S, Gomes ALC, Devlin SM, Shah GL, Sung AD, Sauter CS, Landau HJ, Dahi PB, Perales MA, Chung DJ, Lesokhin AM, Dai A, Clurman A, Slingerland JB, Slingerland AE, Brereton DG, Giardina PA, Maloy M, Armijo GK, Rondon-Clavo C, Fontana E, Bohannon L, Ramalingam S, Bush AT, Lew MV, Messina JA, Littmann E, Taur Y, Jenq RR, Chao NJ, Giralt S, Markey KA, Pamer EG, van den Brink MRM, and Peled JU
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- Adult, Aged, Female, Humans, Male, Middle Aged, Transplantation, Homologous, Feces microbiology, Gastrointestinal Microbiome, Hematopoietic Stem Cell Transplantation
- Abstract
We previously described clinically relevant reductions in fecal microbiota diversity in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous HCT (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma, and amyloidosis in an observational study conducted at 2 transplantation centers in the United States. By using 16S ribosomal gene sequencing, we assessed fecal microbiota composition and diversity, as measured by the inverse Simpson index. At both centers, the diversity of early pretransplant fecal microbiota was lower in patients than in healthy controls and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to those with allo-HCT. Above-median fecal intestinal diversity in the periengraftment period was associated with decreased risk of death or progression (progression-free survival hazard ratio, 0.46; 95% confidence interval, 0.26-0.82; P = .008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and posttransplant outcomes should be undertaken., (© 2021 by The American Society of Hematology.)
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- 2021
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11. The clinical implications of clonal hematopoiesis in hematopoietic cell transplantation.
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Nawas MT, Schetelig J, Damm F, Levine RL, Perales MA, Giralt SA, VanDenBrink MR, Arcila ME, Zehir A, Papaemmanuil E, Klussmeier A, Schmidt AH, Maiwald S, Bolton KL, and Tamari R
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- Clinical Decision-Making, Disease Management, Disease Progression, Graft vs Host Disease etiology, Hematologic Diseases diagnosis, Hematologic Diseases etiology, Hematologic Diseases mortality, Hematologic Diseases therapy, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Humans, Prognosis, Tissue Donors, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Clonal Hematopoiesis, Hematopoiesis, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods
- Abstract
Clonal hematopoiesis (CH) describes somatic mutations in hematopoietic stem and progenitor cells resulting in clonal expansion in individuals with no overt hematologic disease. Since CH increases in an age-related manner, understanding its role in hematopoietic cell transplantation (HCT) has become increasingly relevant to an aging transplant population. Multiple factors distinguish post-transplant hematopoiesis from unperturbed, steady-state hematopoiesis, including the influence of immunosuppressants, cytotoxic reagents, and marked proliferative stress, all of which may enhance or diminish the opportunity for clonal expansion. We reviewed the available clinical evidence on the consequences of CH at time of transplant in patients undergoing autologous HCT, and the impact of donor and recipient CH on allogeneic HCT outcomes. In the absence of evidence-based guidelines, we share our suggestions for managing donors and recipients found to have CH. Large-scale studies are needed to guide an evidence-based, uniform approach for the management of CH in the setting of HCT., (Copyright © 2020. Published by Elsevier Ltd.)
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- 2021
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12. The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD.
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Markey KA, Schluter J, Gomes ALC, Littmann ER, Pickard AJ, Taylor BP, Giardina PA, Weber D, Dai A, Docampo MD, Armijo GK, Slingerland AE, Slingerland JB, Nichols KB, Brereton DG, Clurman AG, Ramos RJ, Rao A, Bush A, Bohannon L, Covington M, Lew MV, Rizzieri DA, Chao N, Maloy M, Cho C, Politikos I, Giralt S, Taur Y, Pamer EG, Holler E, Perales MA, Ponce DM, Devlin SM, Xavier J, Sung AD, Peled JU, Cross JR, and van den Brink MRM
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- Adult, Allografts, Bacteria isolation & purification, Bacteria metabolism, Case-Control Studies, Chronic Disease, Dysbiosis etiology, Dysbiosis microbiology, Feces microbiology, Graft vs Host Disease blood, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Metabolome, Ribotyping, Butyrates blood, Gastrointestinal Microbiome, Graft vs Host Disease microbiology, Propionates blood
- Abstract
Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs., (© 2020 by The American Society of Hematology.)
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- 2020
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13. Vitiligo Following Autologous Hematopoietic Stem Cell Transplantation.
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Nguyen J, Singh N, Afifi S, Giralt S, Lacouture ME, Busam KJ, and Hassoun H
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- Autografts, Female, Humans, Lenalidomide adverse effects, Middle Aged, Multiple Myeloma pathology, Vitiligo pathology, Hematopoietic Stem Cell Transplantation, Lenalidomide administration & dosage, Multiple Myeloma therapy, Vitiligo etiology
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- 2020
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14. Compliments to complement blockade for TA-TMA.
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Scordo M and Giralt S
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- Child, Cohort Studies, Complement System Proteins, Humans, Antibodies, Monoclonal, Humanized, Thrombotic Microangiopathies
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- 2020
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15. Phase I Study of Selinexor, Ixazomib, and Low-dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma.
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Salcedo M, Lendvai N, Mastey D, Schlossman J, Hultcrantz M, Korde N, Mailankody S, Lesokhin A, Hassoun H, Smith E, Shah U, Diab V, Werner K, Landau H, Lahoud O, Drullinsky P, Shah G, Chung D, Scordo M, Giralt S, and Landgren O
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols pharmacology, Boron Compounds pharmacology, Dexamethasone pharmacology, Female, Glycine pharmacology, Glycine therapeutic use, Humans, Hydrazines pharmacology, Male, Middle Aged, Multiple Myeloma drug therapy, Neoplasm Recurrence, Local, Triazoles pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Boron Compounds therapeutic use, Dexamethasone therapeutic use, Glycine analogs & derivatives, Hydrazines therapeutic use, Triazoles therapeutic use
- Published
- 2020
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16. CAR-T - and a side order of IgG, to go? - Immunoglobulin replacement in patients receiving CAR-T cell therapy.
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Hill JA, Giralt S, Torgerson TR, and Lazarus HM
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- Agammaglobulinemia pathology, Antigens, CD19 analysis, B-Lymphocytes pathology, Disease Management, Humans, Immunotherapy, Adoptive methods, Neoplasms complications, Neoplasms pathology, Agammaglobulinemia etiology, Agammaglobulinemia therapy, Immunoglobulin G therapeutic use, Immunotherapy, Adoptive adverse effects, Neoplasms therapy
- Abstract
The development and regulatory approval of chimeric antigen receptor T cell (CAR-T) therapies targeting the B-lineage surface antigen CD19 represents a major milestone in cancer immunotherapy. This treatment also results in depletion of normal CD19+ B cells and is associated with hypogammaglobulinemia. These on-target, off-tumor toxicities may result in an increased risk for infection, particularly for encapsulated bacteria. Data regarding the efficacy and cost-effectiveness of prophylactic IgG replacement in CD19-targeted CAR-T cell therapy recipients is lacking, and current expert recommendations are extrapolated from the data for individuals with primary immune deficiencies. This article reviews CAR-T cell therapies targeting B-lineage lymphocytes, associated side effects, and considerations for the approach to management of hypogamaglobulinemia in this patient population. Studies are needed to establish evidence-based approaches to prophylactic immunoglobulin administration in this context, and strategies may differ by patient and CAR-T cell product characteristics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
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- 2019
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17. Measurement of the DNA alkylating agents busulfan and melphalan in human plasma by mass spectrometry.
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Schofield RC, Landau HJ, Giralt SA, Shah GL, Scordo M, Lin A, Zanutto E, Ramanathan LV, Pessin MS, and Carlow DC
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- Chromatography, High Pressure Liquid methods, DNA chemistry, Humans, Alkylating Agents blood, Busulfan blood, Immunosuppressive Agents blood, Melphalan blood, Tandem Mass Spectrometry methods
- Abstract
Busulfan and melphalan are cytotoxic DNA alkylating agents that are used in many hematopoietic stem cell transplantation (HCT) conditioning regimens. We report the development of an assay using turbulent flow liquid chromatography (TFLC) and tandem mass spectrometry to simultaneously measure the concentration of busulfan (Bu) and melphalan (Mel) in human plasma. The method involves precipitating proteins in the plasma specimen with an organic solvent containing deuterated internal standards of both compounds. Following centrifugation, an aliquot of the supernatant was injected into the TFLC mass spectrometry system operated in the positive ion mode. The analytical measurement range for both compounds was 10-5000 ng/mL, and with validated dilutions the reportable range was extended to 25,000 ng/mL. Intra-day and inter-day (n = 20 day) precision studies showed a coefficient of variation (CV) of <7% at several concentrations across the measurement range. To determine accuracy recovery studies were performed at several concentrations spanning the measurement range. Recoveries for both compounds were between 98 and 103%. Additionally, busulfan was compared with an existing assay and showed excellent correlation. Experiments were conducted to rule out matrix effects, carryover and interference from endogenous substances. The validated clinically reportable range (CRR) and assay precision will allow this assay to be used clinically to monitor and adjust Mel and Bu levels to ensure better therapeutic outcomes and also to support clinical trials aimed at better defining therapeutic ranges., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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18. CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma.
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Sauter CS, Senechal B, Rivière I, Ni A, Bernal Y, Wang X, Purdon T, Hall M, Singh AN, Szenes VZ, Yoo S, Dogan A, Wang Y, Moskowitz CH, Giralt S, Matasar MJ, Perales MA, Curran KJ, Park J, Sadelain M, and Brentjens RJ
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local therapy, Transplantation, Autologous methods, Treatment Outcome, Immunotherapy, Adoptive methods, Lymphoma, Large B-Cell, Diffuse therapy, Receptors, Antigen, T-Cell therapeutic use, Stem Cell Transplantation methods
- Abstract
High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography-positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 10
6 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell-induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence ( P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation ( P < .001) and possibly interleukin-10 ( P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%). Subjects given decreased naive-like (CD45RA+ CCR7+ ) CD4+ and CD8+ CAR T cells experienced superior PFS ( P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566., (© 2019 by The American Society of Hematology.)- Published
- 2019
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19. Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States.
- Author
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Muffly L, Pasquini MC, Martens M, Brazauskas R, Zhu X, Adekola K, Aljurf M, Ballen KK, Bajel A, Baron F, Battiwalla M, Beitinjaneh A, Cahn JY, Carabasi M, Chen YB, Chhabra S, Ciurea S, Copelan E, D'Souza A, Edwards J, Foran J, Freytes CO, Fung HC, Gale RP, Giralt S, Hashmi SK, Hildebrandt GC, Ho V, Jakubowski A, Lazarus H, Luskin MR, Martino R, Maziarz R, McCarthy P, Nishihori T, Olin R, Olsson RF, Pawarode A, Peres E, Rezvani AR, Rizzieri D, Savani BN, Schouten HC, Sabloff M, Seftel M, Seo S, Sorror ML, Szer J, Wirk BM, Wood WA, and Artz A
- Subjects
- Aged, Cohort Studies, Demography, Female, Hematopoietic Stem Cell Transplantation mortality, Humans, Male, Multivariate Analysis, Prognosis, Time Factors, Transplantation, Homologous mortality, Treatment Outcome, United States, Hematopoietic Stem Cell Transplantation statistics & numerical data
- Abstract
In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time ( P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.
- Published
- 2017
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20. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel.
- Author
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de Witte T, Bowen D, Robin M, Malcovati L, Niederwieser D, Yakoub-Agha I, Mufti GJ, Fenaux P, Sanz G, Martino R, Alessandrino EP, Onida F, Symeonidis A, Passweg J, Kobbe G, Ganser A, Platzbecker U, Finke J, van Gelder M, van de Loosdrecht AA, Ljungman P, Stauder R, Volin L, Deeg HJ, Cutler C, Saber W, Champlin R, Giralt S, Anasetti C, and Kröger N
- Subjects
- Humans, Risk Factors, Transplantation Conditioning, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myelomonocytic, Chronic therapy, Myelodysplastic Syndromes therapy, Practice Guidelines as Topic
- Abstract
An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with ≥10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DLI strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT., (© 2017 by The American Society of Hematology.)
- Published
- 2017
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21. Myeloid-derived suppressor cells: The green light for myeloma immune escape.
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Malek E, de Lima M, Letterio JJ, Kim BG, Finke JH, Driscoll JJ, and Giralt SA
- Subjects
- Humans, Multiple Myeloma immunology, Myeloid-Derived Suppressor Cells metabolism
- Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous, immature myeloid cell population with the ability to suppress innate and adaptive immune responses that promote tumor growth. MDSCs are increased in patients with multiple myeloma (MM) and have bidirectional interaction with tumors within the MM microenvironment. MM-MDSCs promote MM tumor growth and induce immune suppression; conversely, MM cells induce MDSC development and survival. Although the role of MDSCs in infections, inflammatory diseases and solid tumors has been extensively characterized, their tumor-promoting and immune-suppressive role in MM and the MM microenvironment is only beginning to emerge. The presence and activation of MDSCs in MM patients has been well documented; however, the direct actions and functional consequences of MDSCs on cancer cells is poorly defined. Immunosuppressive MDSCs play an important role in tumor progression primarily because of their capability to promote immune-escape, angiogenesis, drug resistance and metastasis. However, their role in the bone marrow (BM), the primary MM site, is poorly understood. MM remains an incurable malignancy, and it is likely that the BM microenvironment protects MM against chemotherapy agents and the host immune system. A growing body of evidence suggests that host immune cells with a suppressive phenotype contribute to a myeloma immunosuppressive network. Among the known suppressor cells, MDSCs and T regulatory cells (Tregs) have been found to be significantly increased in myeloma patients and their levels correlate with disease stage and clinical outcome. Furthermore, it has been shown that MDSC can mediate suppression of myeloma-specific T-cell responses through the induction of T-cell anergy and Treg development in the MM microenvironment. Here, we review clinical correlations and the preclinical proof-of-principle data on the role of MDSCs in myeloma immunotolerance and highlight the mechanistically relevant MDSC-targeted compounds and their potential utility in a new approach for anti-myeloma therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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22. Phase IB study of cabozantinib in patients with relapsed and/or refractory multiple myeloma.
- Author
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Lendvai N, Yee AJ, Tsakos I, Alexander A, Devlin SM, Hassoun H, Korde N, Lesokhin AM, Landau H, Mailankody S, Koehne G, Chung DJ, Landgren O, Raje NS, and Giralt S
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Anilides therapeutic use, Multiple Myeloma drug therapy, Neoplasm Recurrence, Local drug therapy, Protein Kinase Inhibitors therapeutic use, Pyridines therapeutic use, Receptor Protein-Tyrosine Kinases antagonists & inhibitors
- Published
- 2016
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23. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.
- Author
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Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, Grupp SA, Guinan EC, Martin PL, Steinbach G, Krishnan A, Nemecek ER, Giralt S, Rodriguez T, Duerst R, Doyle J, Antin JH, Smith A, Lehmann L, Champlin R, Gillio A, Bajwa R, D'Agostino RB Sr, Massaro J, Warren D, Miloslavsky M, Hume RL, Iacobelli M, Nejadnik B, Hannah AL, and Soiffer RJ
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Cohort Studies, Female, Hepatic Veno-Occlusive Disease complications, Hepatic Veno-Occlusive Disease diagnosis, Hepatic Veno-Occlusive Disease epidemiology, Humans, Infant, Infant, Newborn, Male, Middle Aged, Multiple Organ Failure diagnosis, Multiple Organ Failure epidemiology, Multiple Organ Failure etiology, Severity of Illness Index, Young Adult, Fibrinolytic Agents therapeutic use, Hepatic Veno-Occlusive Disease drug therapy, Multiple Organ Failure drug therapy, Polydeoxyribonucleotides therapeutic use
- Abstract
Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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24. Phase I/II Trial of Paclitaxel With Ifosfamide Followed by High-Dose Paclitaxel, Ifosfamide, and Carboplatin (TI-TIC) With Autologous Stem Cell Reinfusion for Salvage Treatment of Germ Cell Tumors.
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Feldman DR, Glezerman I, Patil S, Van Alstine L, Bajorin DF, Fischer P, Hughes A, Sheinfeld J, Bains M, Reich L, Woo K, Giralt S, Bosl GJ, and Motzer RJ
- Subjects
- Adult, Carboplatin adverse effects, Drug Administration Schedule, Female, Humans, Ifosfamide adverse effects, Male, Middle Aged, Paclitaxel adverse effects, Prospective Studies, Salvage Therapy, Stem Cell Transplantation, Transplantation, Autologous, Treatment Outcome, Young Adult, Carboplatin administration & dosage, Ifosfamide administration & dosage, Neoplasms, Germ Cell and Embryonal drug therapy, Neoplasms, Germ Cell and Embryonal surgery, Paclitaxel administration & dosage
- Abstract
Background: Salvage high-dose (HD) chemotherapy with autologous stem cell transplant (ASCT), consisting of 2 to 3 sequential cycles of HD carboplatin and etoposide (CE) can achieve durable remissions in approximately half of patients with relapsed germ cell tumors. To improve on these results and based on success with paclitaxel, ifosfamide, and cisplatin (TIP) as salvage conventional-dose chemotherapy, we conducted a phase I/II trial of HD paclitaxel with ifosfamide (TI), substituting carboplatin for cisplatin to allow dose escalation., Patients and Methods: Treatment consisted of 1 to 2 cycles of TI and granulocyte colony-stimulating factor for stem cell mobilization followed by 3 cycles of HD TI with carboplatin (TIC) with ASCT every 21 to 28 days. Twenty-six patients were enrolled. For phase I, a standard 3+3 dose-escalation design was used., Results: With no dose-limiting toxicities observed, the maximum tolerated dose (MTD) was not reached and the highest prespecified dose level (paclitaxel 250 mg/m(2), ifosfamide 9990 mg/m(2), carboplatin area under the curve 24) was considered the MTD. In phase II, a Simon 2-stage design was used to estimate the complete response (CR) rate at the MTD. With 7 of 11 phase II patients who achieved a CR, efficacy was demonstrated. However, 3 patients developed delayed chronic kidney disease, resulting in premature trial closure., Conclusion: TI-TIC was active in relapsed germ cell tumors but treatment-emergent chronic renal impairment, possibly from overlapping ifosfamide and carboplatin, preclude its further use. TI-CE, consisting of 2 cycles of TI with 3 cycles of HD CE remains the standard of care HD chemotherapy regimen at Memorial Sloan Kettering Cancer Center., Competing Interests: The authors declare no conflict of interest., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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25. High day 28 ST2 levels predict for acute graft-versus-host disease and transplant-related mortality after cord blood transplantation.
- Author
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Ponce DM, Hilden P, Mumaw C, Devlin SM, Lubin M, Giralt S, Goldberg JD, Hanash A, Hsu K, Jenq R, Perales MA, Sauter C, van den Brink MR, Young JW, Brentjens R, Kernan NA, Prockop SE, O'Reilly RJ, Scaradavou A, Paczesny S, and Barker JN
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Cord Blood Stem Cell Transplantation mortality, Female, Graft vs Host Disease mortality, HLA Antigens metabolism, Hematologic Neoplasms blood, Humans, Infant, Interleukin-1 Receptor-Like 1 Protein, Interleukin-8 metabolism, Male, Middle Aged, Neutrophils metabolism, Receptors, Tumor Necrosis Factor, Type I metabolism, Retrospective Studies, Time Factors, Transplantation Conditioning, Young Adult, Biomarkers blood, Cord Blood Stem Cell Transplantation adverse effects, Graft vs Host Disease diagnosis, Hematologic Neoplasms mortality, Hematologic Neoplasms therapy, Receptors, Cell Surface blood
- Abstract
While cord blood transplantation (CBT) is an effective therapy for hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated if biomarkers could predict aGVHD and TRM after day 28 in CBT recipients. Day 28 samples from 113 CBT patients were analyzed. Suppressor of tumorigenicity 2 (ST2) was the only biomarker associated with grades II-IV and III-IV aGVHD and TRM. Day 180 grade III-IV aGVHD in patients with high ST2 levels was 30% (95% confidence interval [CI], 18-43) vs 13% (95% CI, 5-23) in patients with low levels (P = .024). The adverse effect of elevated ST2 was independent of HLA match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95% CI, 13-35) vs 5% (95% CI, 1-13) if levels were low (P = .001). GVHD was the most common cause of death in high ST2 patients. High concentrations of tumor necrosis factor receptor-1, interleukin-8, and regenerating islet-derived protein 3-α were also associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and further improve survival after CBT., (© 2015 by The American Society of Hematology.)
- Published
- 2015
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26. Dominant unit CD34+ cell dose predicts engraftment after double-unit cord blood transplantation and is influenced by bank practice.
- Author
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Purtill D, Smith K, Devlin S, Meagher R, Tonon J, Lubin M, Ponce DM, Giralt S, Kernan NA, Scaradavou A, Stevens CE, and Barker JN
- Subjects
- Adolescent, Adult, Aged, Antigens, CD34 metabolism, Biomarkers metabolism, Blood Preservation methods, Cell Separation methods, Child, Child, Preschool, Cryopreservation methods, Graft Survival, Humans, Infant, Middle Aged, Young Adult, Blood Banking methods, Cord Blood Stem Cell Transplantation methods, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation methods, Neutrophils transplantation
- Abstract
We investigated the unit characteristics associated with engraftment after double-unit cord blood (CB) transplantation (dCBT) and whether these could be reliably identified during unit selection. Cumulative incidence of neutrophil engraftment in 129 myeloablative dCBT recipients was 95% (95% confidence interval: 90-98%). When precryopreservation characteristics were analyzed, the dominant unit CD34(+) cell dose was the only characteristic independently associated with engraftment (hazard ratio, 1.43; P = .002). When postthaw characteristics were also included, only dominant unit infused viable CD34(+) cell dose independently predicted engraftment (hazard ratio, 1.95; P < .001). We then examined the determinants of infused viable CD34(+) cell dose (precryopreservation count, postthaw recovery, and postthaw viability) in 402 units thawed at our center. This revealed close correlation between precryopreservation and postthaw CD34(+) cell counts (r(2) = 0.73). Median CD34(+) cell recovery was 101%, although it ranged from 12% to 1480%. Notably, units from non-Netcord Foundation for the Accreditation of Cellular Therapy (Netcord-FACT)-accredited banks were more likely to have low recovery (P < .001). Furthermore, although median postthaw CD34(+) cell viability was 92%, 33 (8%) units had <75% viable CD34(+) cells. Units from non-Netcord-FACT-accredited banks and units with cryovolumes other than 24.5 to 26.0 mL were more likely to have poor postthaw viability. Precryopreservation CD34(+) cell dose and banking practices should be incorporated into CB unit selection., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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27. Optimal screening for geriatric assessment in older allogeneic hematopoietic cell transplantation candidates.
- Author
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Holmes HM, Des Bordes JK, Kebriaei P, Yennu S, Champlin RE, Giralt S, and Mohile SG
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Sensitivity and Specificity, Texas, Disability Evaluation, Frail Elderly statistics & numerical data, Geriatric Assessment methods, Geriatric Assessment statistics & numerical data, Hematopoietic Stem Cell Transplantation statistics & numerical data
- Abstract
Objective: Older patients who receive hematopoietic cell transplantation (HCT) may be at risk for adverse outcomes due to age-related conditions or frailty. Geriatric assessment (GA) has been used to evaluate HCT candidates but can be time-consuming. We therefore sought to determine the predictive ability of two screening tools, the Vulnerable Elders Survey (VES-13) and the G8, for abnormal GA or frailty., Materials and Methods: We enrolled 50 allogeneic HCT candidates age ≥60 years. The GA included measures of medical, physical, functional, and social health. Frailty was defined as 3 or more abnormalities on grip strength, gait speed, weight loss, exhaustion, and activity. We associated baseline characteristics and abnormal GA or frailty. We determined the sensitivity and predictive ability of the VES-13 and G8 for GA and frailty., Results: Overall, 33 (66%) patients (mean age 65.4 years) had an abnormal GA, and 11 patients (22%) were frail. The G8 screening tool had a higher sensitivity for an abnormal GA (69.7%), and the VES-13 had a higher specificity (100%). Both tools had similar discriminatory ability., Conclusions: Older HCT candidates had a significant number of deficits on baseline GA and a high prevalence of frailty. Existing screening tools may not be able to replace a full GA., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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28. Identifying professional education gaps and barriers in multiple myeloma patient care: findings of the Managing Myeloma Continuing Educational Initiative Advisory Committee.
- Author
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Raje N, Faiman B, Harvey RD, Kurtin SE, Lonial S, Kumar SK, Cohen AD, Conde MA, Giralt SA, Recine MS, Tombler ER, Stadtmauer E, Jagannath S, and Anderson KC
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Asymptomatic Diseases, Caregivers, Clinical Trials as Topic, Disease Management, Drug Administration Routes, Drug Approval, Evidence-Based Medicine, Forecasting, Guideline Adherence, Hematology methods, Hematology trends, Hematopoietic Stem Cell Transplantation, Humans, Medical Oncology methods, Medical Oncology trends, Molecular Targeted Therapy, Monoclonal Gammopathy of Undetermined Significance diagnosis, Monoclonal Gammopathy of Undetermined Significance therapy, Multiple Myeloma diagnosis, Multiple Myeloma mortality, Multiple Myeloma nursing, Practice Guidelines as Topic, Therapies, Investigational, United States, United States Food and Drug Administration, Education, Medical, Continuing organization & administration, Hematology education, Medical Oncology education, Multiple Myeloma therapy, Practice Patterns, Physicians' statistics & numerical data, Practice Patterns, Physicians' trends
- Abstract
Advances in the past decade and a half have led to unprecedented improved outcomes for patients with multiple myeloma (MM), and this disease appears to be transitioning to one more characteristic of a chronic disease in large part due to rapid translation of clinical insights into practice at the community level. Although evidence-based guidelines and consensus recommendations remain an important resource for managing cancer patients, they do not fill the gap between the principles of disease management today and the translation of tailoring treatment for individual patient needs. Thus, there is a continuing need for concise, focused educational activities and resources that facilitate improved knowledge and understanding of appropriate, individualized therapeutic strategies for assessing and caring for patients with MM. The next several years will truly be a time of shifting paradigms in the treatment of MM in which new agents will be approved, response criteria will be updated, and new approaches to risk assessment and monitoring minimal residual disease will evolve and enter practice. New groundbreaking therapeutic approaches, such as immunotherapy, might result in significant changes in how MM is treated and managed over the entire life cycle of the disease. Even the definition of the disease might be further amended as insights grow regarding who should be treated and who might benefit more from observation. As such, oncology clinicians will have to carefully review and update their management approaches accordingly even as they begin to focus even more on the survivorship needs of their MM patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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29. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation.
- Author
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Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, No D, Gobourne A, Viale A, Dahi PB, Ponce DM, Barker JN, Giralt S, van den Brink M, and Pamer EG
- Subjects
- Adult, Bacteria classification, Bacteria genetics, Feces microbiology, Female, Hematopoietic Stem Cell Transplantation mortality, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Multivariate Analysis, Outcome Assessment, Health Care methods, Outcome Assessment, Health Care statistics & numerical data, Phylogeny, Prognosis, Proportional Hazards Models, RNA, Ribosomal, 16S genetics, Survival Rate, Transplantation, Homologous, Gastrointestinal Tract microbiology, Genetic Variation, Hematopoietic Stem Cell Transplantation methods, Microbiota genetics
- Abstract
Highly diverse bacterial populations inhabit the gastrointestinal tract and modulate host inflammation and promote immune tolerance. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the gastrointestinal mucosa is damaged, and colonizing bacteria are impacted, leading to an impaired intestinal microbiota with reduced diversity. We examined the impact of intestinal diversity on subsequent mortality outcomes following transplantation. Fecal specimens were collected from 80 recipients of allo-HSCT at the time of stem cell engraftment. Bacterial 16S rRNA gene sequences were characterized, and microbial diversity was estimated using the inverse Simpson index. Subjects were classified into high, intermediate, and low diversity groups and assessed for differences in outcomes. Mortality outcomes were significantly worse in patients with lower intestinal diversity; overall survival at 3 years was 36%, 60%, and 67% for low, intermediate, and high diversity groups, respectively (P = .019, log-rank test). Low diversity showed a strong effect on mortality after multivariate adjustment for other clinical predictors (transplant related mortality: adjusted hazard ratio, 5.25; P = .014). In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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30. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma.
- Author
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Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, Redling K, Koehne G, Chung DJ, Schaffer WL, and Giralt SA
- Subjects
- Aged, Aged, 80 and over, Boronic Acids therapeutic use, Bortezomib, Disease Progression, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Lenalidomide, Male, Middle Aged, Multiple Myeloma genetics, Oligopeptides adverse effects, Pyrazines therapeutic use, Risk Factors, Thalidomide analogs & derivatives, Thalidomide therapeutic use, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols adverse effects, Dexamethasone administration & dosage, Multiple Myeloma drug therapy, Oligopeptides administration & dosage
- Abstract
Standard carfilzomib (20 mg/m(2) cycle 1, 27 mg/m(2) thereafter; 2- to 10-minute infusion) is safe and effective in relapsed or refractory multiple myeloma (R/RMM). We report phase 2 results of carfilzomib 20 mg/m(2) on days 1 to 2 of cycle 1, 56 mg/m(2) thereafter (30-minute infusion), in R/RMM with the option of adding dexamethasone (20 mg) for suboptimal response/progression. Forty-four patients enrolled, all having prior bortezomib and immunomodulatory drugs and a median of 5 prior regimens. Of 42 response-evaluable patients, 23 (55%) achieved at least partial response (PR). Median (95% confidence interval) duration of response, progression-free, and overall survival were 11.7 (6.7-14.7), 4.1 (2.5-11.8), and 20.3 months (6.4-not estimable), respectively. High-risk cytogenetics did not impact outcomes. Treatment was active in bortezomib-refractory subgroups, but these patients tended to have poorer outcomes. Four/10 patients with prior allogeneic transplant achieved at least PR. Of 6 patients who responded, progressed and had dexamethasone added, 4 achieved at least stable disease. The most frequent grade 3/4 adverse events (AEs) possibly related to carfilzomib included lymphopenia (43%), thrombocytopenia (32%), hypertension (25%), pneumonia (18%), and heart failure (11%). Seven patients (16%) discontinued treatment due to AEs. Carfilzomib 56 mg/m(2) ± dexamethasone was tolerable and provided durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01351623., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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31. The future of autologous stem cell transplantation in myeloma.
- Author
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van Rhee F, Giralt S, and Barlogie B
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials as Topic, Combined Modality Therapy, Disease-Free Survival, Humans, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Neoplasm, Residual, Remission Induction, Transplantation, Autologous, Treatment Outcome, Multiple Myeloma therapy, Stem Cell Transplantation trends
- Abstract
Autologous stem cell transplantation (ASCT) has long been considered frontline therapy for newly diagnosed myeloma patients. This Spotlight examines the role of ASCT in the era of novel drugs and argues that ASCT should continue to be considered for eligible patients. A combination of novel drugs with ASCT in a sequential treatment approach can attain long-term survival and perhaps cure a subset of patients. ASCT will likely remain an important platform to develop curative strategies in the foreseeable future., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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32. BRAF V600E mutation and clonal evolution in a patient with relapsed refractory myeloma with plasmablastic differentiation.
- Author
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Bohn OL, Hsu K, Hyman DM, Pignataro DS, Giralt S, and Teruya-Feldstein J
- Subjects
- Amino Acid Substitution, Clonal Evolution, Drug Resistance, Neoplasm, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Male, Middle Aged, Multiple Myeloma metabolism, Multiple Myeloma therapy, Neoplasm Recurrence, Local, Plasma Cells pathology, Proto-Oncogene Proteins B-raf metabolism, Cell Differentiation genetics, Multiple Myeloma genetics, Mutation, Plasma Cells metabolism, Proto-Oncogene Proteins B-raf genetics
- Published
- 2014
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33. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation.
- Author
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Pemmaraju N, Tanaka MF, Ravandi F, Lin H, Baladandayuthapani V, Rondon G, Giralt SA, Chen J, Pierce S, Cortes J, Kantarjian H, Champlin RE, De Lima M, and Qazilbash MH
- Subjects
- Adolescent, Adult, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local surgery, Recurrence, Retrospective Studies, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation methods, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute surgery
- Abstract
Background: Outcomes in patients with acute promyelocytic leukemia (APL) have improved; however, a significant number of patients still relapse despite receiving all-trans-retinoic acid (ATRA) and arsenic-based therapies., Patients and Methods: Outcomes of patients with relapsed APL who were treated at our institution (1980-2010) and who received HCT were compared with those who received chemotherapy (CT) only., Results: Among 40 patients, 24 received HCT (autologous [auto] HCT, 7; allogeneic [allo] HCT, 14; both, 3); 16 received CT only. The median age at diagnosis was 36 years (range, 13-50 years), 31 years (range, 16-58 years), and 44 years (range, 24-79 years) for the auto-HCT, allo-HCT, and CT groups, respectively. Ten (100%) patients who received auto-HCT and 12 (71%) who received allo-HCT were in complete remission at the time of the HCT. The median follow-ups in the auto-HCT, allo-HCT, and CT groups were 74 months (range, 26-135 months), 118 months (range, 28-284 months), and 122 months (range, 32-216 months), respectively. Transplantation-related mortality (1 year) after auto-HCT and allo-HCT were 10% and 29%, respectively. The 7-year event-free survival after auto-HCT and allo-HCT was 68.6% and 40.6%, respectively (P = .45). The 7-year overall survival was 85.7%, 49.4%, and 40% in the auto-HCT, allo-HCT, and CT groups, respectively (P = .48)., Conclusion: Both auto-HCT and allo-HCT are associated with durable remission and prolonged survival. All 3 strategies (auto-HCT, allo-HCT, CT) were found to be feasible in the relapsed APL setting and result in long-term disease control in selected patients. In this retrospective analysis, overall survival for patients who received HCT was not significantly better than patients who received CT only, but a trend toward better outcomes was seen in patients who underwent auto-HCT, although not statistically significant., (Published by Elsevier Inc.)
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- 2013
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34. Authors' reply to Tendas et al.
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Cohen MZ, Rozmus CL, Mendoza TR, Padhye NS, Neumann J, Gning I, Aleman A, Giralt S, and Cleeland CS
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- Female, Humans, Male, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation psychology, Neoplasms therapy, Quality of Life
- Published
- 2013
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35. Symptoms and quality of life in diverse patients undergoing hematopoietic stem cell transplantation.
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Cohen MZ, Rozmus CL, Mendoza TR, Padhye NS, Neumann J, Gning I, Aleman A, Giralt S, and Cleeland CS
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- Adult, Aged, Culture, Ethnicity, Female, Graft vs Host Disease epidemiology, Humans, Language, Linear Models, Longitudinal Studies, Male, Middle Aged, Quality of Health Care, Sex Factors, Socioeconomic Factors, Young Adult, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation psychology, Neoplasms therapy, Quality of Life
- Abstract
Context: Symptoms and quality of life (QOL) are critically important in hematopoietic stem cell transplantation (HSCT). However, few studies have examined these factors by transplant type among diverse cultures., Objectives: To identify and compare QOL and symptom severity and prevalence by transplant type in a diverse population having HSCT., Methods: The M. D. Anderson Symptom Inventory Blood and Marrow Transplantation (MDASI-BMT) module measured symptom severity and its impact. The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) measured QOL., Results: Symptom data were collected from 164 patients at eight points (pretransplant to 100 days post-transplant) and QOL data at four times. Over time, symptom severity was significantly correlated with QOL and patients who had allogeneic transplants with myeloablative regimens showed more severe sleep disturbance and poorer QOL than patients having autologous transplants. Male patients reported less fatigue than female patients. However, ethnicity was not significant. Patients whose functional status was good had fewer of the five worst symptoms and higher QOL than patients with a poor functional status. Patients with acute graft-versus-host disease had more severe symptoms than those who did not., Conclusion: Type of transplant and preparative regimen are the most important aspects to consider when managing symptoms and QOL. This information is important for providing anticipatory guidance and support needed during the transplantation experience, to explore in future research the mechanisms involved in symptoms after HSCT, and to develop additional effective interventions., (Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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36. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era.
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Warlick E, Ahn KW, Pedersen TL, Artz A, de Lima M, Pulsipher M, Akpek G, Aljurf M, Cahn JY, Cairo M, Chen YB, Cooper B, Deol A, Giralt S, Gupta V, Khoury HJ, Kohrt H, Lazarus HM, Lewis I, Olsson R, Pidala J, Savani BN, Seftel M, Socié G, Tallman M, Ustun C, Vij R, Vindeløv L, and Weisdorf D
- Subjects
- Adult, Aged, Benzamides, Female, Graft vs Host Disease mortality, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Middle Aged, Neoplasm Recurrence, Local mortality, Protein Kinase Inhibitors therapeutic use, Survival Rate, Transplantation, Homologous, Unrelated Donors, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Neoplasm Recurrence, Local prevention & control, Piperazines therapeutic use, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrimidines therapeutic use, Transplantation Conditioning
- Abstract
Tyrosine kinase inhibitors (TKIs) and reduced intensity conditioning (RIC)/nonmyeloablative (NMA) conditioning hematopoietic cell transplants (HCTs) have changed the therapeutic strategy for chronic myelogenous leukemia (CML) patients. We analyzed post-HCT outcomes of 306 CML patients reported to the Center for International Blood and Marrow Transplant Research aged 40 years and older undergoing RIC/NMA HCT from 2001 to 2007: 117 (38%) aged 40 to 49 years, 119 (39%) 50 to 59 years, and 70 (23%) 60 years or older. The majority (74%) had treatment with imatinib before HCT. At HCT, most patients aged 40 to 49 years were in chronic phase (CP) 1 (74%), compared with 31% aged 60 years or older. Siblings were donors for 56% aged 40 to 49 years; older cohorts had more unrelated donors. The majority received peripheral blood grafts and RIC across all age groups. 3 year overall survival (54%, 52%, and 41%), day + 100 grade II-IV acute GVHD (26%, 32%, and 32%), chronic GVHD (58%, 51%, and 43%), and 1-year treatment-related mortality (18%, 20%, and 13%) were similar across ages. The 3-year relapse incidence (36%, 43%, and 66%) and disease-free survival (35%, 32%, and 16%) were inferior in the oldest cohort. Importantly, for CP1 patients, relapse and disease-free survival were similar across age cohorts. Allogeneic RIC HCT for older patients with CML can control relapse with acceptable toxicity and survival in TKI-exposed CML, especially if still in CP1.
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- 2012
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37. ATG and RIC: not such a good match?
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Giralt S
- Published
- 2011
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38. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3.
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Dimopoulos M, Kyle R, Fermand JP, Rajkumar SV, San Miguel J, Chanan-Khan A, Ludwig H, Joshua D, Mehta J, Gertz M, Avet-Loiseau H, Beksaç M, Anderson KC, Moreau P, Singhal S, Goldschmidt H, Boccadoro M, Kumar S, Giralt S, Munshi NC, and Jagannath S
- Subjects
- Chromosome Aberrations, Humans, Immunoglobulin Light Chains analysis, Multiple Myeloma genetics, Multiple Myeloma immunology, Multiple Myeloma therapy, Myeloma Proteins analysis, Paraproteinemias diagnosis, Paraproteinemias genetics, Paraproteinemias immunology, Paraproteinemias therapy, Prognosis, Recurrence, Multiple Myeloma diagnosis
- Abstract
A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum β(2)-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse.
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- 2011
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39. Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations.
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Jabbour E, Cortes J, Santos FP, Jones D, O'Brien S, Rondon G, Popat U, Giralt S, Kebriaei P, Jones RB, Kantarjian H, Champlin R, and de Lima M
- Subjects
- Adult, Antineoplastic Agents therapeutic use, Catalytic Domain genetics, Cohort Studies, Female, Fusion Proteins, bcr-abl antagonists & inhibitors, Fusion Proteins, bcr-abl chemistry, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Male, Middle Aged, Protein Structure, Tertiary genetics, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases chemistry, Transplantation, Homologous, Treatment Failure, Treatment Outcome, Young Adult, Drug Resistance, Neoplasm genetics, Fusion Proteins, bcr-abl genetics, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Mutation physiology, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases genetics
- Abstract
Hematopoietic stem cell transplantation (HSCT) is effective therapy for patients with chronic myelogenous leukemia (CML) but is now mostly indicated for patients who develop resistance to tyrosine kinase inhibitors (TKIs), which can be associated with point mutations in BCR-ABL1. We reviewed the outcomes of imatinib-resistant CML patients (chronic phase, n = 34; accelerated phase [AP], n = 9; and blast phase [BP], n = 4) who underwent HSCT and had BCR-ABL1 sequencing. Mutations were found in 19 patients (40%); 15 of 19 had advanced CML (AP + BP + second chronic phase). Patients with mutations were more likely to transform to AP/BP at time of imatinib failure (69% vs 35%, P = .03). Forty-two patients (89%) responded to HSCT: 32 (68%) had at least a major molecular response. The 2-year event-free survival was 36% and 58% (P = .05) for the mutant and nonmutant groups, respectively; and the 2-year overall survival was 44% and 76% (P = .02), respectively. HSCT is an important salvage option for TKI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT. HSCT should be considered early for patients deemed to have a low probability of responding to second-generation TKI.
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- 2011
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40. Influence of infused cell dose and HLA match on engraftment after double-unit cord blood allografts.
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Avery S, Shi W, Lubin M, Gonzales AM, Heller G, Castro-Malaspina H, Giralt S, Kernan NA, Scaradavou A, and Barker JN
- Subjects
- Adolescent, Adult, Aged, Cell Count, Child, Child, Preschool, Graft Survival immunology, HLA Antigens analysis, Humans, Infant, Infusions, Intravenous, Middle Aged, Neutrophils immunology, Transplantation, Homologous immunology, Young Adult, Cord Blood Stem Cell Transplantation methods, Hematopoietic Stem Cells cytology, Histocompatibility Testing methods
- Abstract
The influence of cell dose and human leukocyte antigen (HLA) match on double-unit cord blood (CB) engraftment is not established. Therefore, we analyzed the impact of cell dose and high-resolution HLA match on neutrophil engraftment in 84 double-unit CB transplant recipients. The 94% sustained engraftment rate was accounted for by 1 unit in nearly all patients. Higher CD3(+) cell doses (P = .04) and percentage of CD34(+) cell viability (P = .008) were associated with unit dominance. After myeloablative conditioning, higher dominant unit total nucleated cell (TNC), CD34(+) cell, and colony-forming unit doses were associated with higher sustained engraftment and faster neutrophil recovery (P = .07, P = .0008, and P < .0001, respectively). Total infused TNC (P = .0007) and CD3(+) cell doses (P = .001) also significantly influenced engraftment. At high-resolution extensive donor-recipient HLA disparity was frequent, but had no influence on engraftment (P = .66), or unit dominance (P = .13). Although the unit-unit HLA match also did not affect sustained engraftment (P = 1.0), recipients of units closely (7-10 to 10-10) HLA-matched to each other were more likely to demonstrate initial engraftment of both units (P < .0001). Our findings have important implications for unit selection and provide further insight into double-unit biology.
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- 2011
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41. TMLI: a better TBI or more of the same?
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Giralt S
- Published
- 2011
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42. A TAD better for myeloma therapy?
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Giralt S
- Abstract
In this issue of Blood, Lokhorst and colleagues report on the results of HOVON-50, a phase 3 randomized trial designed to evaluate the effects of thalidomide during induction treatment and as maintenance in patients with multiple myeloma. There were 556 patients randomly assigned either to 3 cycles of VAD or to TAD. All patients were to receive high-dose melphalan with autologous stem cell support followed by maintenance with interferon for the VAD arm or thalidomide for the TAD arm.(1) This study together with other randomized and nonrandomized trials establish a definitive role for thalidomide as induction therapy in conjunction with dexamethasone, anthracyclines, and alkylating agents.
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- 2010
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43. Donor-recipient mismatches in MHC class I chain-related gene A in unrelated donor transplantation lead to increased incidence of acute graft-versus-host disease.
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Parmar S, Del Lima M, Zou Y, Patah PA, Liu P, Cano P, Rondon G, Pesoa S, de Padua Silva L, Qazilbash MH, Hosing C, Popat U, Kebriaei P, Shpall EJ, Giralt S, Champlin RE, Stastny P, and Fernandez-Vina M
- Subjects
- Adolescent, Adult, Aged, Female, Genotype, Graft Rejection, Histocompatibility Testing, Humans, Incidence, Male, Middle Aged, Prognosis, Prospective Studies, Risk Factors, Survival Rate, Treatment Outcome, Young Adult, Blood Donors, Genes, MHC Class I genetics, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Hematopoietic Stem Cell Transplantation, Histocompatibility, Leukemia, Myeloid, Acute therapy
- Abstract
The polymorphic products of major histocompatibility complex class I-related chain A (MICA) genes are important in solid organ transplantation rejection. MICA expression is limited to gut epithelium and may play a role in triggering acute graft-versus-host disease (aGVHD). A total of 236 recipients of unrelated donor transplantation were studied. Donor-recipient human leukocyte antigen (HLA) match was 10/10 human leukocyte antigen (HLA-A, -B, -C, -DRB1, -DQB1) in 73% and MICA mismatch in 8.4%. Because of physical vicinity of the loci, MICA mismatch was significantly associated with mismatch at HLA-B and HLA-C. A higher rate of grade II-IV aGVHD was seen in MICA-mismatched patients (80% vs 40%, P = .003) irrespective of degree of HLA matching (HLA 10/10 match: 75% vs 39%, P = .02) and HLA any mismatch (83% vs 46%, P = .003). The rate of grade II-IV gastrointestinal aGVHD was also higher in MICA-mismatched patients (35% vs 17%, P = .05). We conclude that MICA may represent novel a transplantation antigen recognized by human allogeneic T cells. This study was registered at ClinicalTrials.gov (Identifier NCT00506922).
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- 2009
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44. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens.
- Author
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Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, Lentzsch S, Munshi N, Niesvizky R, San Miguel J, Ludwig H, Bergsagel L, Blade J, Lonial S, Anderson KC, Tosi P, Sonneveld P, Sezer O, Vesole D, Cavo M, Einsele H, Richardson PG, Durie BG, and Rajkumar SV
- Subjects
- Antineoplastic Agents therapeutic use, Bortezomib, Clinical Trials as Topic, Combined Modality Therapy methods, Consensus Development Conferences as Topic, Humans, Immunosuppressive Agents therapeutic use, Lenalidomide, Boronic Acids therapeutic use, Hematopoietic Stem Cell Mobilization methods, Hematopoietic Stem Cell Transplantation methods, Medical Oncology methods, Multiple Myeloma therapy, Pyrazines therapeutic use, Thalidomide analogs & derivatives, Thalidomide therapeutic use
- Abstract
The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.
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- 2009
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45. Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma.
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Tam CS, Bassett R, Ledesma C, Korbling M, Alousi A, Hosing C, Kebraei P, Harrell R, Rondon G, Giralt SA, Anderlini P, Popat U, Pro B, Samuels B, Hagemeister F, Medeiros LJ, Champlin RE, and Khouri IF
- Subjects
- Adult, Aged, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Feasibility Studies, Female, Humans, Lymphoma, Mantle-Cell mortality, Male, Middle Aged, Prognosis, Radiotherapy Dosage, Retrospective Studies, Risk Factors, Rituximab, Survival Rate, Transplantation, Autologous, Treatment Outcome, Graft vs Host Disease therapy, Hematopoietic Stem Cell Transplantation, Lymphoma, Mantle-Cell therapy, Transplantation Conditioning
- Abstract
In this study, we analyzed the long-term outcome of a risk-adapted transplantation strategy for mantle cell lymphoma in 121 patients enrolled in sequential transplantation protocols. Notable developments over the 17-year study period were the addition of rituximab to chemotherapy and preparative regimens and the advent of nonmyeloablative allogeneic stem cell transplantation (NST). In the autologous transplantation group (n = 86), rituximab resulted in a marked improvement in progression-free survival for patients who received a transplant in their first remission (where a plateau emerged at 3-8 years) but did not change the outcomes for patients who received a transplant beyond their first remission. In the NST group, composed entirely of patients who received a transplant beyond their first remission, durable remissions also emerged in progression-free survival at 5 to 9 years. The major determinants of disease control after NST were the use of a peripheral blood stem cell graft and donor chimerism of at least 95%, whereas the major determinant of death was immunosuppression for chronic graft-versus-host disease. Our results show that long-term disease-free survival in mantle cell lymphoma is possible after rituximab-containing autologous transplantation for patients in first remission and after NST for patients with relapsed or refractory disease.
- Published
- 2009
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46. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia.
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Lee SJ, Kukreja M, Wang T, Giralt SA, Szer J, Arora M, Woolfrey AE, Cervantes F, Champlin RE, Gale RP, Halter J, Keating A, Marks DI, McCarthy PL, Olavarria E, Stadtmauer EA, Abecasis M, Gupta V, Khoury HJ, George B, Hale GA, Liesveld JL, Rizzieri DA, Antin JH, Bolwell BJ, Carabasi MH, Copelan E, Ilhan O, Litzow MR, Schouten HC, Zander AR, Horowitz MM, and Maziarz RT
- Subjects
- Adolescent, Adult, Aged, Benzamides, Child, Child, Preschool, Disease-Free Survival, Female, HLA Antigens metabolism, Humans, Imatinib Mesylate, Male, Middle Aged, Registries, Treatment Outcome, Antineoplastic Agents therapeutic use, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Piperazines therapeutic use, Pyrimidines therapeutic use
- Abstract
Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM(+)) and 900 subjects who did not receive IM before HCT (IM(-)) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM(+) and IM(-) groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.
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- 2008
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47. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab.
- Author
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Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS, Medeiros LJ, Fayad L, Samaniego F, Alousi A, Anderlini P, Couriel D, de Lima M, Giralt S, Neelapu SS, Ueno NT, Samuels BI, Hagemeister F, Kwak LW, and Champlin RE
- Subjects
- Adult, Aged, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, B-Lymphocytes cytology, Combined Modality Therapy, Cyclophosphamide adverse effects, Female, Follow-Up Studies, Graft vs Host Disease, Graft vs Tumor Effect, Humans, Male, Middle Aged, Myeloablative Agonists adverse effects, Prospective Studies, Recurrence, Remission Induction, Rituximab, Survival Rate, Transplantation Chimera, Transplantation, Homologous, Vidarabine administration & dosage, Vidarabine adverse effects, Antibodies, Monoclonal administration & dosage, Cyclophosphamide administration & dosage, Hematopoietic Stem Cell Transplantation, Lymphoma, Follicular drug therapy, Myeloablative Agonists administration & dosage, Transplantation Conditioning methods, Vidarabine analogs & derivatives
- Abstract
Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m(2) daily for 3 days), cyclophosphamide (750 mg/m(2) daily for 3 days), and rituximab (375 mg/m(2) for 1 day plus 1000 mg/m(2) for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n = 45) or unrelated donors (n = 2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.
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- 2008
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48. Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences.
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Sorror ML, Giralt S, Sandmaier BM, De Lima M, Shahjahan M, Maloney DG, Deeg HJ, Appelbaum FR, Storer B, and Storb R
- Subjects
- Humans, Prevalence, Prognosis, Remission Induction, Sensitivity and Specificity, Survival Rate, Comorbidity, Hematopoietic Stem Cell Transplantation mortality, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Severity of Illness Index
- Abstract
A new hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was effective in predicting outcomes among patients with hematologic malignancies who underwent HCT at Fred Hutchinson Cancer Research Center (FHCRC). Here, we compared the performance of the HCT-CI to 2 other indices and then tested its capacity to predict outcomes among 2 cohorts of patients diagnosed with a single disease entity, acute myeloid leukemia in first complete remission, who underwent transplantation at either FHCRC or M. D. Anderson Cancer Center (MDACC). FHCRC patients less frequently had unfavorable cytogenetics (15% versus 36%) and HCT-CI scores of 3 or more (21% versus 58%) compared with MDACC patients. We found that the HCT-CI had higher sensitivity and outcome predictability compared with the other indices among both cohorts. HCT-CI scores of 0, 1 to 2, and 3 or more predicted comparable nonrelapse mortality (NRM) among FHCRC and MDACC patients. In multivariate models, HCT-CI scores were associated with the highest hazard ratios (HRS) for NRM and survival among each cohort. The 2-year survival rates among FHCRC and MDACC patients were 71% versus 56%, respectively. After adjustment for risk factors, including HCT-CI scores, no difference in survival was detected (HR: 0.98, P = .94). The HCT-CI is a sensitive and informative tool for comparing trial results at different institutions. Inclusion of comorbidity data in HCT trials provides valuable, independent information.
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- 2007
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49. Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia.
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Kebriaei P, Detry MA, Giralt S, Carrasco-Yalan A, Anagnostopoulos A, Couriel D, Khouri IF, Anderlini P, Hosing C, Alousi A, Champlin RE, and de Lima M
- Subjects
- Adolescent, Adult, Aged, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Therapy, Combination, Female, Follow-Up Studies, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Melphalan administration & dosage, Middle Aged, Myeloablative Agonists administration & dosage, Recurrence, Retrospective Studies, Survival Analysis, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Transplantation Conditioning methods, Transplantation, Homologous
- Abstract
Allogeneic hematopoietic stem-cell transplantation (HSCT) remains an effective strategy for inducing durable remission in chronic myeloid leukemia (CML). Reduced-intensity conditioning (RIC) regimens extend HSCT to older patients and those with comorbidities who would otherwise not be suitable candidates for HSCT. The long-term efficacy of this approach is not established. We evaluated outcomes of 64 CML patients with advanced-phase disease (80% beyond first chronic phase), not eligible for myeloablative preparative regimens due to older age or comorbid conditions, who were treated with fludarabine-based RIC regimens. Donor type was matched related (n =30), 1 antigen-mismatched related (n =4), or matched unrelated (n =30). With median follow-up of 7 years, overall survival (OS) and progression-free survival (PFS) were 33% and 20%, respectively, at 5 years. Incidence of treatment-related mortality (TRM) was 33%, 39%, and 48% at 100 days, and 2 and 5 years after HSCT, respectively. In multivariate analysis, only disease stage at time of HSCT was significantly predictive for both OS and PFS. RIC HSCT provides adequate disease control in chronic-phase CML patients, but alternative treatment strategies need to be explored in patients with advanced disease. TRM rates are acceptable in this high-risk population but increase over time.
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- 2007
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50. Hyperacute GVHD: risk factors, outcomes, and clinical implications.
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Saliba RM, de Lima M, Giralt S, Andersson B, Khouri IF, Hosing C, Ghosh S, Neumann J, Hsu Y, De Jesus J, Qazilbash MH, Champlin RE, and Couriel DR
- Subjects
- Acute Disease, Adult, Aged, Female, Graft vs Host Disease drug therapy, Graft vs Host Disease mortality, Humans, Male, Middle Aged, Multivariate Analysis, Prognosis, Retrospective Studies, Risk Factors, Transplantation, Homologous, Treatment Outcome, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Acute graft-versus-host disease (GVHD) is a major limiting factor in allogeneic hematopoietic stem cell transplantation (HSCT), and the timing of acute GVHD may affect patient outcomes. We evaluated the incidence, risk factors, clinical manifestations, and outcomes of hyperacute GVHD, defined as that occurring within 14 days after transplantation, among 809 consecutive HSCTs at the University of Texas M.D. Anderson Cancer Center. Of 265 patients with grade II-IV acute GVHD, 27% had biopsy-proven hyperacute GVHD. Skin involvement was significantly more common (88% versus 44%) and more severe (stage III-IV, 88% versus 66%) in the hyperacute group compared with acute GVHD diagnosed after day 14. On multivariate analysis, significant risk factors for hyperacute GVHD included a mismatched related or matched unrelated donor, a myeloablative conditioning regimen, more than 5 prior chemotherapy regimens, and donor-recipient sex mismatch. Hyperacute GVHD was associated with a significantly lower response rate to first-line therapy and a higher rate of nonrelapse mortality in patients with a mismatched related or matched unrelated donor graft. In conclusion, hyperacute GVHD accounts for a substantial proportion of grade II-IV acute GVHD after HSCT. Patients at high risk or with a diagnosis of hyperacute GVHD should be included in clinical studies.
- Published
- 2007
- Full Text
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