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1. Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Author

Morschhauser, Franck, Fowler, Nathan H, Feugier, Pierre, Bouabdallah, Reda, Tilly, Hervé, Palomba, M Lia, Fruchart, Christophe, Libby, Edward N, Casasnovas, Rene-Olivier, Flinn, Ian W, Haioun, Corinne, Maisonneuve, Hervé, Ysebaert, Loic, Bartlett, Nancy L, Bouabdallah, Kamal, Brice, Pauline, Ribrag, Vincent, Daguindau, Nicolas, Le Gouill, Steven, Pica, Gian M, Martin Garcia-Sancho, Alejandro, López-Guillermo, Armando, Larouche, Jean-François, Ando, Kiyoshi, Gomes da Silva, Maria, André, Marc, Zachée, Pierre, Sehn, Laurie H, Tobinai, Kensei, Cartron, Guillaume, Liu, David, Wang, Jianming, Xerri, Luc, Salles, Gilles A, Abdel-Samad N, Abdo-Matkiwsky M, Abraham J, Abrisqueta P, Anglaret B, Barnes JA, Benbrahim O, Bierman PJ, Bonnet C, Brault P, Bron D, Brooks BJ Jr, Byeff P, Casanova M, Cheung M, Choudhary Y, Comeau T, Cooper B, Couban S, Cox MC, Crump M, Deau Fischer B, Deconinck E, Deeren D, de la Cruz Vicente F, Delarue R, Del Campo R, Delmer A, Delwail V, Duggan PR, Eisenmann DJRM, El Yamani A, Eradat HA, Fabbro M, Farber C, Fisher DC, Fleischman RA, Fleck E, Fornecker LM, Foussard C, Gabarre J, Gaffar YA, Gallardo D, Ghazal H, Giagounidis A, Gill K, Glaisner S, Gonzalez H, Greenberg RH, Goubran Messiha H, Goy A, Gressin R, Gyan E, Hart LL, Hatake K, Hiddemann W, Hodossy B, Horkheimer I, Hoyer RJ, Huebel K, Ishikawa T, Izutsu K, Jardel H, Jhangiani HS, Johnson N, Joly B, Jourdan E, Kargar Samani K, Kato K, Kiguchi T, Kobayashi T, Kohser F, Koike M, Kouroukis C T, Laferriere N, Lamy de la Chapelle T, Landau DA, Lawler WE, Lemieux B, Levitan DA, Longree L, Lopez J, Mace J, Maerevoet M, Maigre M, Marjanovic Z, Michel J, Mounier C, Muntanola A, Ngirabacu MC, Nicolas-Virelizier E, Novelli S, Offner F, Palomera L, Pandit LH, Panwalkar A, Pierre P, Pignon JM, Pinto A, Plöger C, Pranger D, Quick DP, Reyes EA, Robin V, Robu D, Rodriguez Salazar MJ, Rosen PJ, Rosenbluth J, Sadot-Lebouvier S, Sangha R, Segota Z, Shapira I, Shtivelband M, Simon M, Soekler M, Soubeyran P, Taper J, Tereblo HR, Terol MJ, The AS, Ueda Y, van den Neste E, van Eygen K, van Hoof A, Vanstraelen G, Verner E, Warburton P, Yamamoto G, Yokoyama H, Zerazhi H, Zinzani PL., Morschhauser, Franck, Fowler, Nathan H, Feugier, Pierre, Bouabdallah, Reda, Tilly, Hervé, Palomba, M Lia, Fruchart, Christophe, Libby, Edward N, Casasnovas, Rene-Olivier, Flinn, Ian W, Haioun, Corinne, Maisonneuve, Hervé, Ysebaert, Loic, Bartlett, Nancy L, Bouabdallah, Kamal, Brice, Pauline, Ribrag, Vincent, Daguindau, Nicola, Le Gouill, Steven, Pica, Gian M, Martin Garcia-Sancho, Alejandro, López-Guillermo, Armando, Larouche, Jean-Françoi, Ando, Kiyoshi, Gomes da Silva, Maria, André, Marc, Zachée, Pierre, Sehn, Laurie H, Tobinai, Kensei, Cartron, Guillaume, Liu, David, Wang, Jianming, Xerri, Luc, Salles, Gilles A, Abdel-Samad N, Abdo-Matkiwsky M, Abraham J, Abrisqueta P, Anglaret B, Barnes JA, Benbrahim O, Bierman PJ, Bonnet C, Brault P, Bron D, Brooks BJ Jr, Byeff P, Casanova M, Cheung M, Choudhary Y, Comeau T, Cooper B, Couban S, Cox MC, Crump M, Deau Fischer B, Deconinck E, Deeren D, de la Cruz Vicente F, Delarue R, Del Campo R, Delmer A, Delwail V, Duggan PR, Eisenmann DJRM, El Yamani A, Eradat HA, Fabbro M, Farber C, Fisher DC, Fleischman RA, Fleck E, Fornecker LM, Foussard C, Gabarre J, Gaffar YA, Gallardo D, Ghazal H, Giagounidis A, Gill K, Glaisner S, Gonzalez H, Greenberg RH, Goubran Messiha H, Goy A, Gressin R, Gyan E, Hart LL, Hatake K, Hiddemann W, Hodossy B, Horkheimer I, Hoyer RJ, Huebel K, Ishikawa T, Izutsu K, Jardel H, Jhangiani HS, Johnson N, Joly B, Jourdan E, Kargar Samani K, Kato K, Kiguchi T, Kobayashi T, Kohser F, Koike M, Kouroukis C T, Laferriere N, Lamy de la Chapelle T, Landau DA, Lawler WE, Lemieux B, Levitan DA, Longree L, Lopez J, Mace J, Maerevoet M, Maigre M, Marjanovic Z, Michel J, Mounier C, Muntanola A, Ngirabacu MC, Nicolas-Virelizier E, Novelli S, Offner F, Palomera L, Pandit LH, Panwalkar A, Pierre P, Pignon JM, Pinto A, Plöger C, Pranger D, Quick DP, Reyes EA, Robin V, Robu D, Rodriguez Salazar MJ, Rosen PJ, Rosenbluth J, Sadot-Lebouvier S, Sangha R, Segota Z, Shapira I, Shtivelband M, Simon M, Soekler M, Soubeyran P, Taper J, Tereblo HR, Terol MJ, The AS, Ueda Y, van den Neste E, van Eygen K, van Hoof A, Vanstraelen G, Verner E, Warburton P, Yamamoto G, Yokoyama H, Zerazhi H, Zinzani PL., Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Lymphoma and Myeloma [Houston, TX, USA], The University of Texas M.D. Anderson Cancer Center [Houston], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d’Hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité des hémopathies lymphoïdes [CHU Henri Mondor], CHU Henri Mondor, Service d’Onco-Hématologie [La Roche sur Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service d'onco-hématologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie Clinique [Hôpital Hôtel Dieu, Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Hôtel Dieu, Service Hématologie [CH Métropole Savoie, Chambery], Centre Hospitalier Métropole Savoie [Chambéry], Département d'Hématologie [CHU de Montpellier], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Département d'Hématologie [CH Lyon-Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), RELEVANCE Trial Investigators : Abdel-Samad N, Abdo-Matkiwsky M, Abraham J, Abrisqueta P, Anglaret B, Barnes JA, Benbrahim O, Bierman PJ, Bonnet C, Brault P, Bron D, Brooks BJ Jr, Byeff P, Casanova M, Cheung M, Choudhary Y, Comeau T, Cooper B, Couban S, Cox MC, Crump M, Deau Fischer B, Deconinck E, Deeren D, de la Cruz Vicente F, Delarue R, Del Campo R, Delmer A, Delwail V, Duggan PR, Eisenmann DJRM, El Yamani A, Eradat HA, Fabbro M, Farber C, Fisher DC, Fleischman RA, Fleck E, Fornecker LM, Foussard C, Gabarre J, Gaffar YA, Gallardo D, Ghazal H, Giagounidis A, Gill K, Glaisner S, Gonzalez H, Greenberg RH, Goubran Messiha H, Goy A, Gressin R, Gyan E, Hart LL, Hatake K, Hiddemann W, Hodossy B, Horkheimer I, Hoyer RJ, Huebel K, Ishikawa T, Izutsu K, Jardel H, Jhangiani HS, Johnson N, Joly B, Jourdan E, Kargar Samani K, Kato K, Kiguchi T, Kobayashi T, Kohser F, Koike M, Kouroukis C T, Laferriere N, Lamy de la Chapelle T, Landau DA, Lawler WE, Lemieux B, Levitan DA, Longree L, Lopez J, Mace J, Maerevoet M, Maigre M, Marjanovic Z, Michel J, Mounier C, Muntanola A, Ngirabacu MC, Nicolas-Virelizier E, Novelli S, Offner F, Palomera L, Pandit LH, Panwalkar A, Pierre P, Pignon JM, Pinto A, Plöger C, Pranger D, Quick DP, Reyes EA, Robin V, Robu D, Rodriguez Salazar MJ, Rosen PJ, Rosenbluth J, Sadot-Lebouvier S, Sangha R, Segota Z, Shapira I, Shtivelband M, Simon M, Soekler M, Soubeyran P, Taper J, Tereblo HR, Terol MJ, The AS, Ueda Y, van den Neste E, van Eygen K, van Hoof A, Vanstraelen G, Verner E, Warburton P, Yamamoto G, Yokoyama H, Zerazhi H, Zinzani PL., Bernardo, Elizabeth, CHU Henri Mondor [Créteil], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Hospitalier Départemental Vendée, Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
Adult, Male, medicine.medical_specialty, Neutropenia, Intention to Treat Analysi, Follicular lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, Skin Diseases, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Maintenance therapy, immune system diseases, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Survival rate, Lenalidomide, Lymphoma, Follicular, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocol, business.industry, Skin Disease, General Medicine, Middle Aged, medicine.disease, 3. Good health, Intention to Treat Analysis, Thalidomide, Survival Rate, Regimen, 030220 oncology & carcinogenesis, Rituximab, Female, business, Febrile neutropenia, 030215 immunology, medicine.drug, Human
Abstract

International audience; BACKGROUND:Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma.METHODS:We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigator's choice of one of three rituximab-based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival.RESULTS:A total of 1030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab-lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab-chemotherapy group (P=0.13). The interim 3-year rate of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab-chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab-lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%).CONCLUSIONS:Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).

Published
2018

4. Rituximab Toxicity after Preemptive or Therapeutic Administration for Post-Transplant Lymphoproliferative Disorder.

Author

Kinzel M, Kalra A, Khanolkar RA, Williamson TS, Li N, Khan F, Puckrin R, Duggan PR, Shafey M, and Storek J

Subjects
Humans, Rituximab adverse effects, Herpesvirus 4, Human, Retrospective Studies, Risk Factors, Immunoglobulin G, Immunoglobulin M therapeutic use, Immunoglobulin A therapeutic use, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections drug therapy, Epstein-Barr Virus Infections epidemiology, Lymphoproliferative Disorders epidemiology, Lymphoproliferative Disorders etiology, Lymphoproliferative Disorders drug therapy, Neutropenia complications, Neutropenia drug therapy
Abstract

Rituximab is commonly used as prevention, preemption, or therapeutically for post-transplant lymphoproliferative disorder (PTLD) after hematopoietic cell transplantation (HCT). Although it is generally assumed that rituximab toxicity (ie, infections resulting from hypogammaglobulinemia and neutropenia) is negligible in relation to mortality due to PTLD, limited evidence supports the validity of this assumption. We sought to determine the impact of rituximab on immunoglobulin levels, neutrophil count, infection density, and mortality outcomes. This study retrospectively analyzed 349 HCT recipients, 289 of whom did not receive rituximab and 60 of whom received rituximab preemptively or therapeutically at a median of 55 days post-transplantation. IgM, IgG, and IgA levels at 6 months and 12 months post-transplantation were lower in patients who received rituximab compared with those who did not (significant at P < .05 for IgM and IgA at 6 months and for IgM and IgG at 12 months). Rituximab recipients also had a higher incidence of severe neutropenia (<.5/nl) between 3 and 24 months (subhazard ratio [SHR], 2.3; P = .020). Regarding non-Epstein-Barr viral infections/PTLD, the rituximab group had a higher infection density between 3 and 24 months compared with the no-rituximab group (3.8 versus 1.6 infections per 365 days at risk; incidence rate ratio, 2.2; P < .001). The rituximab group also had a higher incidence of fatal infections (SHR, 3.1; P = .026), higher nonrelapse mortality (SHR, 2.4; P = .006), and higher overall mortality (hazard ratio, 1.7; P = .033). There were no significant between-group differences in the incidence of clinically significant graft-versus-host disease, graft failure, or relapse. Based on this study, rituximab given for PTLD is associated with substantial morbidity and mortality. Whether the benefit of preemptive rituximab outweighs the risk remains to be determined. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Published
2023
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5. Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease.

Author

Khanolkar RA, Tripathi G, Dharmani-Khan P, Dabas R, Kinzel M, Kalra A, Puckrin R, Jimenez-Zepeda V, Jamani K, Duggan PR, Chaudhry A, Bryant A, Stewart DA, Khan FM, and Storek J

Subjects
Humans, Antilymphocyte Serum, Chimerism, Risk Factors, Chronic Disease, Cytomegalovirus, Recurrence, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Cytomegalovirus Infections
Abstract

Background Aims: The value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis., Methods: Blood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD)., Results: Incomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003)., Conclusions: High post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Published
2022
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6. Lentivirus-mediated gene therapy for Fabry disease.

Author

Khan A, Barber DL, Huang J, Rupar CA, Rip JW, Auray-Blais C, Boutin M, O'Hoski P, Gargulak K, McKillop WM, Fraser G, Wasim S, LeMoine K, Jelinski S, Chaudhry A, Prokopishyn N, Morel CF, Couban S, Duggan PR, Fowler DH, Keating A, West ML, Foley R, and Medin JA

Subjects
Adult, Antigens, CD34, Bone Marrow Cells, Fabry Disease genetics, Genetic Vectors, Hematopoietic Stem Cells, Humans, Leukocytes, Male, Middle Aged, Trihexosylceramides blood, Trihexosylceramides urine, Fabry Disease enzymology, Fabry Disease therapy, Genetic Therapy methods, Lentivirus genetics, alpha-Galactosidase genetics, alpha-Galactosidase therapeutic use
Abstract

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34 + -selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb 3 ) and globotriaosylsphingosine (lyso-Gb 3 ) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy.

Published
2021
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7. Hematopoietic cell transplant outcomes after myeloablative conditioning with fludarabine, busulfan, low-dose total body irradiation, and rabbit antithymocyte globulin.

Author

Ousia S, Kalra A, Williamson TS, Prokopishyn N, Dharmani-Khan P, Khan FM, Jimenez-Zepeda V, Jamani K, Duggan PR, Daly A, Russell JA, and Storek J

Subjects
Aged, Antilymphocyte Serum therapeutic use, Busulfan therapeutic use, Humans, Myeloablative Agonists therapeutic use, Neoplasm Recurrence, Local, Retrospective Studies, Transplantation Conditioning, Treatment Outcome, Vidarabine analogs & derivatives, Vidarabine therapeutic use, Whole-Body Irradiation, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation
Abstract

Optimal conditioning and graft-vs-host disease (GVHD) prophylaxis for hematopoietic cell transplantation (HCT) are unknown. Here, we report on outcomes after low toxicity, myeloablative conditioning consisting of fludarabine, busulfan, and 4 Gy total body irradiation, in combination with thymoglobulin and post-transplant methotrexate and cyclosporine. We retrospectively studied 700 patients with hematologic malignancies who received blood stem cells from 7 to 8/8 HLA-matched unrelated or related donors. Median follow-up of surviving patients was 5 years. At 5 years, overall survival (OS), relapse-free survival (RFS), and chronic GVHD/relapse-free survival (cGRFS) were 58%, 55%, and 40%. Risk factors for poor OS, RFS, and cGRFS were (1). high to very high disease risk index (DRI), (2). high recipient age, and (3). cytomegalovirus (CMV)-seropositive recipient with seronegative donor (D-R+). The latter risk factor applied particularly to patients with lymphoid malignancies. Neither donor other than HLA-matched sibling (7-8/8 unrelated) nor one HLA allele mismatch was risk factors for poor OS, RFS, or cGRFS. In conclusion, the above regimen results in excellent long-term outcomes. The outcomes are negatively impacted by older age, high or very high DRI, and CMV D-R+ serostatus, but not by donor unrelatedness or one HLA allele mismatch., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2020
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9. Bone marrow staging of patients with non-Hodgkin lymphoma by flow cytometry: correlation with morphology.

Author

Duggan PR, Easton D, Luider J, and Auer IA

Subjects
Antigens, CD analysis, Biopsy, Flow Cytometry, Humans, Immunophenotyping, Lymphoma, Non-Hodgkin immunology, Neoplasm Staging, Retrospective Studies, Bone Marrow pathology, Lymphoma, Non-Hodgkin pathology
Abstract

Background: Immunophenotypic analysis is an established tool in the diagnosis and classification of many hematolymphoid disorders; however, the role of flow cytometry (FC) in detecting bone marrow involvement during the staging of non-Hodgkin lymphoma (NHL) has yet to be defined., Methods: The authors retrospectively analyzed 157 staging and 70 restaging bone marrow biopsies on which morphologic and FC analyses were performed; these biopsies were taken from 195 consecutive patients. Bone marrow biopsies were blindly and independently reviewed and determined to be positive, negative, or suspicious for morphologic involvement by NHL, with disagreements settled by a third reviewer. A selected panel of monoclonal antibodies was used to determine whether bone marrow involvement was immunophenotypically positive (>5%), minimal (<5%), negative, or nondiagnostic., Results: FC and morphology agreed in 78% of cases (178 of 227: 129 both negative, 49 both positive) and were discrepant in 22% (49 of 227). Seven percent (16 of 227) were morphologically positive but showed no evidence of disease on FC, whereas 12% (27 of 227) were positive by FC but had no morphologic involvement. Of the 162 morphologically negative or suspicious bone marrows, 27 were shown to be involved by FC, resulting in a false-negative detection rate of 17%. Most of these (22 of 27, 81%) had minimal detectable disease. Seven percent of Stage I and 26% of Stage II NHL cases with negative staging bone marrow morphologically were found to be involved by FC., Conclusions: Neither morphologic examination of bone marrow biopsy specimens nor FC alone is adequate to detect all cases of NHL with bone marrow involvement. FC is most sensitive for detecting minimal bone marrow lymphoma, whereas morphology will detect most cases in which involvement is >5%. Cases of early stage NHL with morphologically negative bone marrow could potentially be restaged as Stage IV on the basis of FC results. The clinical importance of minimal bone marrow involvement by NHL needs further evaluation., (Copyright 2000 American Cancer Society.)

Published
2000

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