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In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 58, No. 7 ( 2023-07), p. 820-822

Type of Medium: Online Resource

ISSN: 0268-3369 , 1476-5365

URL: Article

DOI: 10.1038/s41409-023-01976-8

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2004030-1

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2875-2875

Abstract: Abstract 2875 Poster Board II-851 Allogeneic stem cell transplantation followed by donor lymphocyte infusions (DLI) induces a clinical significant graft versus myeloma (GvM) effect in 30-50% of multiple myeloma (MM) patients. Since this effect can be dependent on the presence of host dendritic cells (DC) at the time of DLI, combining DLI with infusion of host DCs may improve GvM effect. To evaluate this we conducted a phase I/II trial in which DLI- non responding MM patients received host monocyte derived DC vaccinations in combination with a second DLI. Patients received 3 DC vaccinations both i.v. and i.d. with two-week intervals. The first vaccination was combined with DLI. Half of the i.d. DCs was loaded with KLH for immunomonitoring purposes. Specific anti-host and anti-KLH T cell responses were monitored using IFN-gamma release and proliferation assays. To date six patients completed all 3 DC vaccinations, one patient received only one vaccination. Exacerbation of mild pre-existing graft versus host disease occurred in two patients after the first and second vaccination respectively; no other adverse events were seen. Starting from the second vaccination patients developed positive skin reactions against KLH-DCs (n=5/6) and against DCs (n=2/5). The delayed type hypersensivity (DTH) skin tests performed after the last vaccination showed positive indurations against host DCs (n=5/5) and against KLH (n=4/5). All patients (n=4/4) developed significant but variable proliferative and IFN-gamma responses against KLH and host DCs. While 5 patients developed no clinical GvM effect, in one patient disease was stabilized for 29 weeks and the cellular responses against host DCs and KLH were still present 20 weeks after the first vaccination. Another patient, who entered the study with minimal residual disease, is clinically stable for 18 weeks now, however he has not yet been evaluated further. We conclude that administration of host DCs combined with DLI is safe and feasible, and that the vaccinations result in enhanced T cell responses. However, clinical GvM effects are limited. This GvM effect may be increased after vaccination with DCs loaded with hematopoietic restricted minor H antigens. Disclosures: Off Label Use: Rituximab, a monoclonal anti-CD20 antibody, is used to deplete B cells in the treatment of chronic GVHD.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.2875.2875

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 604-604

Abstract: Abstract: Here we report for the first time on long term follow-up data of a cohort of 60 patients who received TCRαβ and CD19 depleted peripheral blood stem cell grafts from haploidentical family donors within a prospective, multi-center, single-arm, phase I/II clinical study (EudraCT No.: 2011-005562-38). As planned, 30 pediatric and 30 adult patients were enrolled in this trial: All patients received a reduced-intensity conditioning regimen consisting of fludarabine (160 mg/m2), thiotepa (10 mg/kg), melphalan (140 mg/m2) and either antithymocyte globulin (Grafalon, 15 or 30 mg/kg, N=53) or 7 Gy total nodal irradiation (N=7). MMF (40 mg/kg/day) was administered as single-agent GVHD prophylaxis until Day 30. Results: Sixty patients with a median age of 18.5 years (range 1-63) were treated. Twenty-five patients had AML, 17 ALL, 6 MDS/MPS and 1 each had multiple myeloma and acute undifferentiated leukemia. Six patients had solid tumors (soft tissue sarcomas and neuroblastomas) and 4 non-malignant disorders (SCID, Wiskott-Aldrich syndrome, lysosomal storage disorder and sickle cell anemia). Of the 56 patients with malignant disease, 33 were transplanted in complete (CR), 11 in partial (PR) and 12 in non-remission (NR). Twenty of the 56 patients with malignant diseases received a 2nd or 3rd transplantation within this protocol. In total, 88 depletion procedures were performed with the CliniMACS plus System (Miltenyi Biotec, Germany) at 7 GMP laboratories and resulted in a median T and B cell log depletion of 4.7 (range 3.6-5.3) and 3.4 (range: 2.3-4.5), respectively. The median number of infused CD34+ cells and TCRαβ T cells was 12.4 × 106 /kg BW (range 4.0 - 54.9) and 1.4× 104 /kg BW (range 0.06-6.4), respectively. Engraftment was rapid with a median of 13 (range 9-41) and 15 (11-38) days to reach ANC 〉 500 cell/µl and PLT 〉 20,000 cells/µl. Nine patients rejected the graft. Eight of them were successfully re-transplanted and 1 patient died. One patient received stem cell boosts from the original donor due to poor graft function. On day 100, peripheral T cell chimerism was completely donor-type in 44 of 47 evaluable patients, and mixed in 3. None of the patients developed grade III/IV aGVHD and only 6 patients (10%) had grade II aGVHD. Of 47 evaluable patients 4 had severe cGVHD (9%), and 6 (13%) and 5 (11%) had moderate and mild cGVHD, respectively. CMV reactivation was seen in 25 (42%) mainly adult patients, and only 1 (2%) patient developed disease. Twenty-one (35%) patients had ADV reactivation and 7 children and 1 adult (13%) developed disease. Only 1 case of EBV disease (encephalitis) occurred (2%). A median of 221 (range 8-1230) CD3+ cells/µl was reached on day 100. The median numbers of CD3/CD4+ and CD3/CD8+ cells at 1 year post transplant were 316 (range 1-1173) and 308 (range 0-2203) /µl. As of July 15 2018, 57 patients have completed the 2 year follow-up, died or discontinued the study resulting in a median follow-up of 706 days (range 18-800). 37 patients (62%) are alive and 23 (38%) died. Relapse was the major cause of death (N=12) followed by ADV infection (N=3), ARDS (N=3) and 1 case each of cardiac arrest, multi organ failure, sepsis due to graft failure and demyelinating neuropathy. Cause of death was not reported in 1 patient. Eight of the 20 patients who received the 2nd or 3rd transplantation are alive; 1 discontinued the study prematurely. Of the 23 patients transplanted in PR or NR, 13 are alive. The Kaplan-Meier estimated probabilities of overall survival, disease-free survival (DFS) were 62% and 53%, respectively. Cumulative incidences of relapse and NRM at 2 years were 34% and 20%, respectively. For those patients with leukemia receiving a first SCT in CR, the overall survival, DFS and relapse rate were 75%, 64% and 20%, respectively. Conclusion: The transplantation of TCRαβ and CD19 depleted haploidentical hematopoietic stem cell grafts was safe and feasible. Decentralized production using the CliniMACS System was feasible and reliably resulted in grafts containing sufficient numbers of stem cells with only minimal numbers of co-infused TCRαβ T cells. None of the patients developed grade III-IV aGVHD and incidence of cGVHD was acceptable. Given the heterogeneous patient cohort with respect to age, disease, remission status and number of previous transplants, the outcome of patients after 2 years follow-up is promising. Disclosures Lang: Miltenyi Biotec: Patents & Royalties, Research Funding. Handgretinger:Miltenyi Biotec: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding. Meisel:Amgen: Consultancy. Mielke:KIADIS Pharma: Speakers Bureau; Miltenyi Biotec: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau; Celgene: Speakers Bureau. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Bader:Neovii: Research Funding; Medac: Patents & Royalties, Research Funding; Riemser: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Kuball:Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gd T cells and receptors and isolation strategies, Research Funding; Miltenyi Biotec: Research Funding; Novartis: Research Funding. Bonig:Miltenyi Biotec GmbH: Honoraria, Research Funding. Karitzky:Miltenyi Biotec GmbH: Employment. Holtkamp:Miltenyi Biotec GmbH: Employment. Malchow:Miltenyi Biotec GmbH: Employment. Siewert:Miltenyi Biotec GmbH: Employment. Biedermann:Miltenyi Biotec GmbH: Employment. Bethge:Neovii GmbH: Honoraria, Research Funding; Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-110124

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 5, No. 1 ( 2021-01-12), p. 240-249

Abstract: We conducted a multicenter prospective single-arm phase 1/2 study that assesses the outcome of αβ T-cell depleted allogeneic hematopoietic stem cell transplantation (allo-HSCT) of peripheral blood derived stem cells from matched related, or unrelated donors (10/10 and 9/10) in adults, with the incidence of acute graft-versus-host disease (aGVHD) as the primary end point at day 100. Thirty-five adults (median age, 59; range, 19-69 years) were enrolled. Conditioning consisted of antithymocyte globulin, busulfan, and fludarabine, followed by 28 days of mycophenolic acid after allo-HSCT. The minimal follow-up time was 24 months. The median number of infused CD34+ cells and αβ T cells were 6.1 × 106 and 16.3 × 103 cells per kg, respectively. The cumulative incidence (CI) of aGVHD grades 2-4 and 3-4 at day 100 was 26% and 14%. One secondary graft failure was observed. A prophylactic donor lymphocyte infusion (DLI) (1 × 105 CD3+ T cells per kg) was administered to 54% of the subjects, resulting in a CI of aGVHD grades 2-4 and 3-4 to 37% and 17% at 2 years. Immune monitoring revealed an early reconstitution of natural killer (NK) and γδ T cells. Cytomegalovirus reactivation associated with expansion of memory-like NK cells. The CI of relapse was 29%, and the nonrelapse mortality 32% at 2 years. The 2-year CI of chronic GVHD (cGVHD) was 23%, of which 17% was moderate. We conclude that only 26% of patients developed aGVHD 2-4 after αβ T-cell–depleted allo-HSCT within 100 days and was associated with a low incidence of cGVHD after 2 years. This trial was registered at www.trialregister.nl as #NL4767.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2020002444

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2063-2063

Abstract: αβT- cell depleted allogeneic haematopoietic stem cell transplantations (allo-SCT) have so far been reported in haploidentical stem cell transplantations. First results have been promising with a good engraftment and low incidence of GVHD. However, high rates of life-threatening GVHD are still observed within the context of matched related (MRD) and unrelated (MUD) donors. Therefore we aimed to assess the feasibility of αβT-cell depletion in the context of MUD and MRD and aimed to establish a transplantation regimen for patients with MRD and MUD undergoing an αβT- cell depleted allo-SCT. Objective To test feasibility of the generation of αβT- cell depleted grafts from MRD and MUD and assess the engraftment in the context of different conditioning regimens after allo-SCT in patients with poor risk leukemia. Method Initial proof runs for the generation of αβT-cell and CD19 depleted grafts have been performed in 4 healthy donors. Grafts for transplantation of the first 5 patients (cohort I) have been depleted with GMP-grade anti-αβTCR and anti-CD19 antibodies. The subsequent grafts for patients in cohort II (n=4) and III (n=2) have been selectively depleted with GMP-grade anti-αβTCRs antibodies. Three conditioning regimens have been investigated (I): fludarabine 120 mg/m2 + cyclophosfamide 4800 mg/m2, (II): fludarabine 120 mg/m2 + busilvex AUC=90 and (III): ATG (Genzyme®) 4 mg/m2 + fludarabine 120 mg/m2 + busilvex AUC=90 followed by αβT- cell depleted grafts from matched related or unrelated donors. No additional immune suppression was given after allo-SCT. Main study parameters/endpoints: (1) Feasibility to generate an αβT-cell depleted graft form MRD and MUD. (2) Engraftment and reconstitution of T-cells within the context of different transplantation regimens. Results Products for 11 patients have been successfully processed and used for αβT-cell depleted allo-SCT between 2011 and 2013. A ∼4 log depletion of αβT-cells has been observed in the product with a recovery of ∼75% of CD34+ cells. In cohort I, primary engraftment (chimerism 〉 95%) was 40%. Engrafted patients showed a rapid reconstitution of γδT-cells and αβT-cells with a broad αβT-cell repertoire as determined by spectratyping. Therefore the next cohort was dose-intensified and the CD19-depletion omitted (cohort II). 75% of cohort II showed a swift engraftment. Again a dominance of γδT-cells was observed which associated with a rapidly reconstituting αβT-cell repertoire. Omitting CD19-depletion did not result in severe EBV-reactivations. One patient had an EBV reactivation under a short course of prednisone; however EBV was rapidly cleared after tapering steroids. In order to further increase engraftment cohort III was additionally treated with an early application of ATG (day -10/-9) and no graft failure has been observed so far. Conclusion αβT-cell depletion is feasible in the context of MRD and MUD. An intensified conditioning with additional host T-cell depletion seems to be beneficial for a profound engraftment. αβT-cell depletion associates with a swift and dominant reconstitution of γδT-cells as well as a rapidly restoring αβT-cell repertoire which is able to control viral re-activations. Disclosures: Kuball: Miltenyi: GMP product development Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2063.2063

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 55, No. 11 ( 2020-11), p. 2188-2192

Type of Medium: Online Resource

ISSN: 0268-3369 , 1476-5365

URL: Article

DOI: 10.1038/s41409-020-0910-9

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2004030-1

In: Journal of the American Academy of Dermatology, Elsevier BV, Vol. 83, No. 2 ( 2020-08), p. 447-454

Type of Medium: Online Resource

ISSN: 0190-9622

URL: Article

DOI: 10.1016/j.jaad.2019.11.038

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2001404-1

In: HemaSphere, Ovid Technologies (Wolters Kluwer Health), Vol. 5, No. 6 ( 2021-06-01), p. e580-

Type of Medium: Online Resource

ISSN: 2572-9241

URL: Article

DOI: 10.1097/HS9.0000000000000580

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2021

detail.hit.zdb_id: 2922183-3

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2164-2164

Abstract: Introduction: We report the first analysis of a multicenter prospective single-arm phase I/II study that assesses the safety and feasibility of transplantation of TCRalpha/beta depleted stem cells from matched related or unrelated donors using the CliniMACS plus System (Miltenyi Biotec, Germany) in combination with a non-myeloablative conditioning in adult patients (trial nr NL48606.000.14). The conditioning regimen consisted of ATG (Thymoglobulin®) 1.5mg/kg i.v. days -12 to -9; fludarabine i.v. 40 mg/m2 days -5 to -2 and busulfan i.v. (Busivex®) days -5 to -2 (cumulative AUC of 80-90mg*h/L), followed by 28 days of mycophenolic acid. All 35 subjects were eligible to address the primary endpoint which is the incidence of acute GVHD at day 100. Results: 2 centers enrolled 10 female and 25 male patients (median age 59 years, range 19 - 69 years), including 9 AML, 4 ALL, 2 CML, 5 MM, 1 NHL, 10 MDS, 4 MPN. Diseases were in CR (n=17), VGPR (n=1), PR (n=5) or non-remission (n=12). 4 subjects had one or more previous allogeneic SCTs. Donors included 4 MRD, 24 10/10 matched MUD and 7 9/10 matched MUD. 8 male patients received stem cells of female donors. The median number of CD34+ cells and αβ TCR cells/kg was 6.1x 10^6 (range, 1.9-10) and 14.5x10^3 (range, 0-136), respectively. One primary graft failure was observed. Primary engraftment of ANCs 〉 500 cells/μL was reached at a median of 14 days (range 9 - 48 days) and of platelets 〉 20 at a median of 17 days (range 10 - 99) days. The median time of follow-up of this first analysis was 190 days (range 110-400 days). 3/35 patients developed acute GVHD grade III-IV during the first 100 days, 9/35 patients developed acute GVHD grade II-IV and 16/35 patients grade I-IV at day 100. At day 100 the cumulative incidence (CI) of CMV was 31%, of EBV 36% and of BK cystitis 20%. The combined CI of CMV/EBV/BK infections with a CTC-AE grade III-V was 53% at day 100. Immune reconstitution was rapid with a median of 227 (range 34 - 1626) CD3+ cells/µl on day 100 but varied substantially between patients. The median numbers of CD3/CD4+ and CD3/CD8+ at day 100 post transplant were 60 (range 30 - 120) and 124 (range 5 - 1450) cells/µl. The median numbers of NK were 289 (range 32-1140) at day 30 and 128 (range 24 - 1228) cells/µl at day 100 post transplant. The median numbers of γδ T cells were 38 (range 4-143) at day 30 and 50 (range 8-556) cells/µl at day 100 post transplant. 26 out of 35 patients were alive, 2 patients died of a relapse, 2 of GVHD and 5 of infectious complications. Kaplan Meier estimates of the OS are 88% (+/- 6%) at day 100 and 68% (+/- 9%) at 1Y. Kaplan Meier estimates of the EFS are 77% (+/- 7%) at day 100 and 52% (+/- 10%) at 1Y. 2 patients developed a relapse before day 100 and 5 patients before 1Y. It is noted that the outcome of 5 patients with MM was very poor in this cohort (3 patients developed a relapse and 2 patients died of complications). Conclusion: Allo-SCT of αβ T cell depleted PBMCs form matched related or unrelated donors, in combination with early ATG and a non-myeloablative conditioning regimen, resulted in favorable rates of primary engraftment (34/35), a CI of aGVHD II-IV of 26% with only minimal immuno-suppression and an encouraging early disease control (Fig 1). OS survival was mainly impacted by NRM (Fig 1), by which the majority of complications were of infectious nature. While all patients with MM suffered from NRM or relapse, all other disease categories had a rather favorable outcome. Reducing inter-individual variations in immune reconstitution early after transplantation will be key to further improve outcomes. Disclosures Minnema: Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Servier: Consultancy. Kuball:Novartis: Research Funding; Miltenyi Biotec: Research Funding; Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gd T cells and receptors and isolation strategies, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-112758

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 57, No. 3 ( 2022-03), p. 423-430

Abstract: Hematopoietic stem cell transplantation (HSCT) from haploidentical donors is a viable option for patients lacking HLA-matched donors. Here we report the results of a prospective multicenter phase I/II trial of transplantation of TCRαβ and CD19-depleted peripheral blood stem cells from haploidentical family donors after a reduced-intensity conditioning with fludarabine, thiotepa, and melphalan. Thirty pediatric and 30 adult patients with acute leukemia ( n  = 43), myelodysplastic or myeloproliferative syndrome ( n  = 6), multiple myeloma ( n  = 1), solid tumors ( n  = 6), and non-malignant disorders ( n  = 4) were enrolled. TCR αβ/CD19-depleted grafts prepared decentrally at six manufacturing sites contained a median of 12.1 × 10 6 CD34 + cells/kg and 14.2 × 10 3 TCRαβ + T-cells/kg. None of the patients developed grade lll/IV acute graft-versus-host disease (GVHD) and only six patients (10%) had grade II acute GVHD. With a median follow-up of 733 days 36/60 patients are alive. The cumulative incidence of non-relapse mortality at day 100, 1 and 2 years after HSCT was 5%, 15%, and 17% for all patients, respectively. Estimated probabilities of overall and disease-free survival at 2 years were 63% and 50%, respectively. Based on these promising results in a high-risk patient cohort, haploidentical HSCT using TCRαβ/CD19-depleted grafts represents a viable treatment option.

Type of Medium: Online Resource

ISSN: 0268-3369 , 1476-5365

URL: Article

DOI: 10.1038/s41409-021-01551-z

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2004030-1