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1. GVHD occurrence does not reduce AML relapse following PTCy-based haploidentical transplantation: a study from the ALWP of the EBMT

Author

Baron, F., Labopin, M., Tischer, J., Raiola, A. M., Vydra, J., Blaise, D., Chiusolo, Patrizia, Stolzel, F., Fanin, R., Chevallier, P., Nagler, A., Ciceri, F., Mohty, M., Chiusolo P. (ORCID:0000-0002-1355-1587), Baron, F., Labopin, M., Tischer, J., Raiola, A. M., Vydra, J., Blaise, D., Chiusolo, Patrizia, Stolzel, F., Fanin, R., Chevallier, P., Nagler, A., Ciceri, F., Mohty, M., and Chiusolo P. (ORCID:0000-0002-1355-1587)

Abstract

The association between graft-versus-host disease (GVHD) occurrence and acute myeloid leukemia (AML) relapse in patients treated with HLA-haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) with post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis has remained debated. Here, we addressed this issue in patients with active AML at transplantation. 2-year cumulative incidences of relapse and leukemia-free survival (LFS) were 49% and 32.3%, respectively. There were no associations between acute nor chronic GVHD of any grade and lower relapse incidence. However, grade I acute GVHD was associated with better LFS (HR = 0.71, 95% CI 0.51–0.99, P = 0.04). In contrast, grade III–IV acute (HR = 3.09, 95% CI 1.87–5.12, P < 0.0001) as well as extensive chronic (HR = 3.3, 95% CI 1.81–6.04, P = 0.0001) GVHD correlated with higher nonrelapse mortality leading to lower LFS (HR = 1.36, 95% CI 0.99–1.86, P = 0.056 and HR = 1.97, 95% CI 1.35–2.89, P = 0.0004, respectively). In conclusion, these data suggest a dissociation of graft-versus-leukemia effects from GVHD in patients with active AML treated with PTCy-based Haplo-HCT.

Published
2023

2. Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT

Author

Noviello, M, Manfredi, F, Ruggiero, E, Perini, T, Oliveira, G, Cortesi, F, De Simone, P, Toffalori, C, Gambacorta, V, Greco, R, Peccatori, J, Casucci, M, Casorati, G, Dellabona, P, Onozawa, M, Teshima, T, Griffioen, M, Halkes, C, Falkenburg, J, Stolzel, F, Altmann, H, Bornhauser, M, Waterhouse, M, Zeiser, R, Finke, J, Cieri, N, Bondanza, A, Vago, L, Ciceri, F, Bonini, C, Noviello M., Manfredi F., Ruggiero E., Perini T., Oliveira G., Cortesi F., De Simone P., Toffalori C., Gambacorta V., Greco R., Peccatori J., Casucci M., Casorati G., Dellabona P., Onozawa M., Teshima T., Griffioen M., Halkes C. J. M., Falkenburg J. H. F., Stolzel F., Altmann H., Bornhauser M., Waterhouse M., Zeiser R., Finke J., Cieri N., Bondanza A., Vago L., Ciceri F., Bonini C., Noviello, M, Manfredi, F, Ruggiero, E, Perini, T, Oliveira, G, Cortesi, F, De Simone, P, Toffalori, C, Gambacorta, V, Greco, R, Peccatori, J, Casucci, M, Casorati, G, Dellabona, P, Onozawa, M, Teshima, T, Griffioen, M, Halkes, C, Falkenburg, J, Stolzel, F, Altmann, H, Bornhauser, M, Waterhouse, M, Zeiser, R, Finke, J, Cieri, N, Bondanza, A, Vago, L, Ciceri, F, Bonini, C, Noviello M., Manfredi F., Ruggiero E., Perini T., Oliveira G., Cortesi F., De Simone P., Toffalori C., Gambacorta V., Greco R., Peccatori J., Casucci M., Casorati G., Dellabona P., Onozawa M., Teshima T., Griffioen M., Halkes C. J. M., Falkenburg J. H. F., Stolzel F., Altmann H., Bornhauser M., Waterhouse M., Zeiser R., Finke J., Cieri N., Bondanza A., Vago L., Ciceri F., and Bonini C.

Abstract

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (T SCM ) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1 + Eomes + T-bet − ) BM-T SCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.

Published
2019

3. Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study

Author

Kayser S, Kramer M, Martinez-Cuadron D, Grenet J, Metzeler K, Sustkova Z, Luskin M, Brunner A, Elliott M, Gil C, Marini S, Racil Z, Cetkovsky P, Novak J, Perl A, Platzbecker U, Stolzel F, Ho A, Thiede C, Stone R, Rollig C, Montesinos P, Schlenk R, and Levis M

Subjects
Adult, Aged, 80 and over, Core Binding Factors, Remission Induction, Hematopoietic Stem Cell Transplantation, Middle Aged, Prognosis, Leukemia, Myeloid, Acute, Young Adult, fms-Like Tyrosine Kinase 3, Mutation, Humans, Aged, Retrospective Studies
Abstract

The aim of this study was to evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia (CBFAML) in an international, multicenter survey of 97 patients of whom 52% had t(8;21)(q22;q22) and 48% had inv(16)(p13q22)/t(16;16)(p13;q22). The median age of the patients was 53 years (range, 19-81). Complete remission after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients, respectively. The median follow-up was 4.43 years (95% confidence interval [95% CI]: 3.35-7.39 years). The median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. Among intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95% CI: 59-100%) as compared to 38% (95% CI: 27-54%; P=0.02) in all other patients with CBFAML/ FLT3-ITD (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (HCT), 12 in first complete remission and 12 after relapse. Allogeneic HCT in first complete remission was not beneficial (P=0.60); however, allogeneic HCT seemed to improve median survival in relapsed patients compared to that of patients treated with chemotherapy (not reached vs. 0.6 years, respectively; P=0.002). Excluding patients with inv(16) with trisomy 22, our data indicate that compathe outcome of CBF-AML patients with FLT3-ITD may be inferior to that of patients without FLT3-ITD (based on previously published data), suggesting that prognostically CBF-AML patients with FLT3-ITD should not be classified as favorable-risk. FLT3-inhibitors may improve the outcome of these patients.

Published
2021

4. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Author

Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., Antin, J.H., et al., Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., and Antin, J.H., et al.

Abstract

Contains fulltext : 190745.pdf (publisher's version ) (Closed access), Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD(+) leukemia cells. This synergized with the allogeneic CD8(+) T cell response, leading to long-term survival in six mouse models of FLT3-ITD(+) AML. Sorafenib-related IL-15 production caused an increase in CD8(+)CD107a(+)IFN-gamma(+) T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD(+) AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8(+) T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

Published
2018

5. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey

Author

Zeiser, R., Burchert, A., Lengerke, C., Verbeek, M.M., Maas-Bauer, K., Metzelder, S.K., Spoerl, S., Ditschkowski, M., Ecsedi, M., Sockel, K., Ayuk, F., Ajib, S., Fontbrune, F.S. de, Na, I.K., Penter, L., Holtick, U., Wolf, D., Schuler, E., Meyer, E., Apostolova, P., Bertz, H., Marks, R., Lubbert, M., Wasch, R., Scheid, C., Stolzel, F., Ordemann, R., Bug, G., Kobbe, G., Negrin, R., Brune, M., Spyridonidis, A., Schmitt-Graff, A., Velden, W.J. van der, Huls, G.A., Mielke, S., Grigoleit, G.U., Kuball, J., Flynn, R., Ihorst, G., Du, J., Blazar, B.R., Arnold, R., Kroger, N., Passweg, J., Halter, J., Socie, G., Beelen, D., Peschel, C., Neubauer, A., Finke, J., Duyster, J., Bubnoff, N. von, Zeiser, R., Burchert, A., Lengerke, C., Verbeek, M.M., Maas-Bauer, K., Metzelder, S.K., Spoerl, S., Ditschkowski, M., Ecsedi, M., Sockel, K., Ayuk, F., Ajib, S., Fontbrune, F.S. de, Na, I.K., Penter, L., Holtick, U., Wolf, D., Schuler, E., Meyer, E., Apostolova, P., Bertz, H., Marks, R., Lubbert, M., Wasch, R., Scheid, C., Stolzel, F., Ordemann, R., Bug, G., Kobbe, G., Negrin, R., Brune, M., Spyridonidis, A., Schmitt-Graff, A., Velden, W.J. van der, Huls, G.A., Mielke, S., Grigoleit, G.U., Kuball, J., Flynn, R., Ihorst, G., Du, J., Blazar, B.R., Arnold, R., Kroger, N., Passweg, J., Halter, J., Socie, G., Beelen, D., Peschel, C., Neubauer, A., Finke, J., Duyster, J., and Bubnoff, N. von

Abstract

Item does not contain fulltext, Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Published
2015

6. MicroRNA-23a mediates post-transcriptional regulation of CXCL12 in bone marrow stromal cells

Author

Arabanian, L. S., primary, Fierro, F. A., additional, Stolzel, F., additional, Heder, C., additional, Poitz, D. M., additional, Strasser, R. H., additional, Wobus, M., additional, Borhauser, M., additional, Ferrer, R. A., additional, Platzbecker, U., additional, Schieker, M., additional, Docheva, D., additional, Ehninger, G., additional, and Illmer, T., additional

Published
2014
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10. HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia

Author

Baron, F., Labopin, M., Tischer, J., Ciceri, F., Raiola, A. M., Blaise, D., Sica, S., Vydra, J., Fanin, R., Diez-Martin, J. L., Bulabois, C. E., Stolzel, F., Busca, A., Jindra, P., Koc, Y., Chevallier, P., Forcade, E., Rosler, W., Passweg, J., Alexander Kulagin, Carella, A. M., Simand, C., Bazarbachi, A., Pioltelli, P., Nagler, A., and Mohty, M.

11. Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT

Author

Masahiro Onozawa, Francesco Manfredi, Marieke Griffioen, Filippo Cortesi, Martin Bornhäuser, Luca Vago, Valentina Gambacorta, Chiara Bonini, Cristina Toffalori, Monica Casucci, Jhf Falkenburg, Raffaella Greco, Giacomo Oliveira, Tommaso Perini, Miguel Waterhouse, Maddalena Noviello, Fabio Ciceri, Jürgen Finke, Takanori Teshima, Constantijn J.M. Halkes, Robert Zeiser, Paolo Dellabona, Giulia Casorati, Pantaleo De Simone, Eliana Ruggiero, Heidi Altmann, Friedrich Stölzel, Attilio Bondanza, Nicoletta Cieri, Jacopo Peccatori, Noviello, M., Manfredi, F., Ruggiero, E., Perini, T., Oliveira, G., Cortesi, F., De Simone, P., Toffalori, C., Gambacorta, V., Greco, R., Peccatori, J., Casucci, M., Casorati, G., Dellabona, P., Onozawa, M., Teshima, T., Griffioen, M., Halkes, C. J. M., Falkenburg, J. H. F., Stolzel, F., Altmann, H., Bornhauser, M., Waterhouse, M., Zeiser, R., Finke, J., Cieri, N., Bondanza, A., Vago, L., Ciceri, F., Bonini, C., Noviello, M, Manfredi, F, Ruggiero, E, Perini, T, Oliveira, G, Cortesi, F, De Simone, P, Toffalori, C, Gambacorta, V, Greco, R, Peccatori, J, Casucci, M, Casorati, G, Dellabona, P, Onozawa, M, Teshima, T, Griffioen, M, Halkes, C, Falkenburg, J, Stolzel, F, Altmann, H, Bornhauser, M, Waterhouse, M, Zeiser, R, Finke, J, Cieri, N, Bondanza, A, Vago, L, Ciceri, F, and Bonini, C

Subjects
0301 basic medicine, Male, Myeloid, T-Lymphocytes, medicine.medical_treatment, Programmed Cell Death 1 Receptor, General Physics and Astronomy, 02 engineering and technology, Hematopoietic stem cell transplantation, Antineoplastic Agent, Receptors, KIR, Recurrence, Retrospective Studie, hemic and lymphatic diseases, CTLA-4 Antigen, lcsh:Science, Hepatitis A Virus Cellular Receptor 2, Transplantation, Homologou, Multidisciplinary, Clonal anergy, Gene Expression Regulation, Leukemic, Remission Induction, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Middle Aged, 021001 nanoscience & nanotechnology, Lymphocyte Activation Gene 3 Protein, 3. Good health, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Bone Marrow Cell, Female, 0210 nano-technology, Human, Signal Transduction, Adult, T cell, Science, Antineoplastic Agents, Bone Marrow Cells, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Antigens, CD, Signaling Lymphocytic Activation Molecule Family, Glucocorticoid-Induced TNFR-Related Protein, medicine, Humans, Transplantation, Homologous, Retrospective Studies, Clonal Anergy, business.industry, General Chemistry, medicine.disease, Transplantation, 030104 developmental biology, T-Lymphocyte, Immunology, lcsh:Q, Bone marrow, business, Immunologic Memory
Abstract

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (TSCM) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1+Eomes+T-bet−) BM-TSCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease., Allogeneic hematopoietic cell transplantation is the standard treatment of acute myeloid leukemia, but many patients relapse. Here the authors show increased markers of exhaustion and cancer antigen specificity within bone marrow-residing memory T cells precede and potentially predict the relapse.

Published
2019
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12. Outcomes following second allogeneic haematopoietic cell transplantation in patients with myelofibrosis: a retrospective study of the Chronic Malignancies Working Party of EBMT

Author

Nicolaus Kröger, Aleksandar Radujkovic, Jakob Passweg, Marie Robin, Tomasz Czerw, Patrick Hayden, Emanuele Angelucci, Alessandro Rambaldi, Katya Mauff, Liesebeth C. de Wreede, Ibrahim Yakoub-Agha, Juan Carlos Hernández-Boluda, Jiri Mayer, Yves Chalandon, Matthias Stelljes, Donal P. McLornan, Uwe Platzbecker, Mitja Nabergoj, Stephen P. Robinson, Xavier Poiré, Linda Koster, Fabio Ciceri, Søren Lykke Petersen, Marco Ladetto, Fridrich Stölzel, Nabergoj, M., Mauff, K., Robin, M., Kroger, N., Angelucci, E., Poire, X., Passweg, J., Radujkovic, A., Platzbecker, U., Robinson, S., Rambaldi, A., Petersen, S. L., Stolzel, F., Stelljes, M., Ciceri, F., Mayer, J., Ladetto, M., de Wreede, L. C., Koster, L., Hayden, P. J., Czerw, T., Hernandez-Boluda, J. C., Mclornan, D., Chalandon, Y., Yakoub-Agha, I., UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre du cancer, UCL - (SLuc) Service d'hématologie, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), and Université Paris Cité (UPCité)

Subjects
medicine.medical_specialty, Graft failure, Transplantation Conditioning, [SDV]Life Sciences [q-bio], Primary Myelofibrosis / therapy, Graft vs Host Disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Neoplasms, medicine, Humans, In patient, Sibling, Myelofibrosis, Retrospective Studies, ddc:616, Transplantation, business.industry, Incidence (epidemiology), Haematopoietic cell transplantation, Hematopoietic Stem Cell Transplantation, Retrospective cohort study, Hematology, Middle Aged, medicine.disease, 3. Good health, surgical procedures, operative, Primary Myelofibrosis, 030220 oncology & carcinogenesis, Chronic gvhd, business, 030215 immunology
Abstract

International audience; Therapeutic management of patients with primary or secondary myelofibrosis (MF) who experience relapse or graft failure following allogeneic haematopoietic cell transplantation (allo-HCT) remains heterogeneous. We retrospectively analyzed 216 patients undergoing a second allo-HCT for either relapse (56%) or graft failure (31%) between 2010 and 2017. Median age was 57.3 years (range 51–63). The same donor as for the first allo-HCT was chosen in 66 patients (31%) of whom 19 received an HLA-identical sibling donor, whereas a different donor was chosen for 116 patients (54%). Median follow-up was 40 months. Three-year overall survival (OS) and relapse-free survival (RFS) were 42% and 39%, respectively. Three-year non-relapse mortality (NRM) and relapse rates were 36% and 25%, respectively. Grade II-IV and III-IV acute GVHD occurred in 25% and 11% of patients, respectively, and the 3-year incidence of chronic GVHD was 33% including 14% for extensive grade. Graft-failure incidence at 1 year was 14%. In conclusion, our data suggest that a second allo-HCT is a potential option for patients failing first allo-HCT for MF albeit careful patient assessment is fundamental to identify individual patients who could benefit from this approach.

Published
2021
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13. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial

Author

Christian Junghanß, Christoph Groth, Nadezda Basara, Sandra Grass, Anja Klein, Inken Hilgendorf, Dietger Niederwieser, Sabine Dressler, Domenico Russo, Matthias Stelljes, Miroslaw Markiewicz, Beate Hauptrock, Daniel Wolff, Christof Scheid, Hélène Labussière-Wallet, Ernst Holler, Wichard Vogel, Peter Dreger, Kerstin Schaefer-Eckart, Heidrun A. Mylius, Goetz Ulrich Grigoleit, Maria Caterina Micò, Joachim Baumgart, Jochen Casper, Fabio Ciceri, Thomas Luft, Dietrich W. Beelen, Anna Paola Iori, Alessandro Rambaldi, Gernot Stuhler, Péter Reményi, Maria Bieniaszewska, Marta Medeot, Tamás Masszi, Nils Rudolf Winkelmann, Udo Holtick, Jacopo Peccatori, Uwe Pichlmeier, Mauricette Michallet, Friedrich Stölzel, Eva Maria Wagner-Drouet, Fabio Benedetti, Stephan Mielke, Johannes Schetelig, Régis Peffault de Latour, Wolfgang Bethge, Georg Nikolaus Franke, Michael Tribanek, Monika Dzierzak-Mietla, Helge Menzel, Gérard Socié, Rudolf Trenschel, Gerald Wulf, Bertram Glass, Christina Grosse-Thie, Mareike Verbeek, Juergen Finke, Francesca Patriarca, Claudia Hemmelmann, Beelen, D. W., Trenschel, R., Stelljes, M., Groth, C., Masszi, T., Remenyi, P., Wagner-Drouet, E. -M., Hauptrock, B., Dreger, P., Luft, T., Bethge, W., Vogel, W., Ciceri, F., Peccatori, J., Stolzel, F., Schetelig, J., Junghanss, C., Grosse-Thie, C., Michallet, M., Labussiere-Wallet, H., Schaefer-Eckart, K., Dressler, S., Grigoleit, G. U., Mielke, S., Scheid, C., Holtick, U., Patriarca, F., Medeot, M., Rambaldi, A., Mico, M. C., Niederwieser, D., Franke, G. -N., Hilgendorf, I., Winkelmann, N. R., Russo, D., Socie, G., Peffault de Latour, R., Holler, E., Wolff, D., Glass, B., Casper, J., Wulf, G., Menzel, H., Basara, N., Bieniaszewska, M., Stuhler, G., Verbeek, M., Grass, S., Iori, A. P., Finke, J., Benedetti, F., Pichlmeier, U., Hemmelmann, C., Tribanek, M., Klein, A., Mylius, H. A., Baumgart, J., Dzierzak-Mietla, M., and Markiewicz, M.

Subjects
Adult, Male, medicine.medical_specialty, Transplantation Conditioning, Population, Medizin, Antineoplastic Agents, Treosulfan, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, education, Busulfan, Preparative Regimen, Aged, education.field_of_study, business.industry, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Interim analysis, 3. Good health, Fludarabine, Transplantation, Regimen, Leukemia, Myeloid, Acute, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Female, business, Vidarabine, 030215 immunology, medicine.drug
Abstract

Background: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. Methods: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18–70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts

Published
2020

14. Post-Transplantation Cyclophosphamide for Graft-versus- Host Disease Prophylaxis in Multiple Myeloma Patients Who Underwent Allogeneic Hematopoietic Cell Transplantation

Author

Firoozeh Sahebi, Jaap van Doesum, Emanuele Angelucci, Fabio Ciceri, Anna Proia, Yener Koc, Didier Blaise, Edouard Forcade, Montserrat Rovira, Simona Sammassimo, Meral Beksac, Linda Koster, Nicolaus Kröger, David Valcárcel, Dirk-Jan Eikema, Friedrich Stölzel, Stefan Schönland, I. Yakoub-Agha, Johanna Tischer, Concepcion Herrera Arroyo, Jaime Sanz, Patrick Hayden, Luca Castagna, James F. Sanchez, Andrew McDonald, Ellen Meijer, Hematology, CCA - Cancer Treatment and quality of life, Sahebi, F., Eikema, D. -J., Koster, L., Kroger, N., Meijer, E., van Doesum, J. A., Rovira, M., Koc, Y., Angelucci, E., Blaise, D., Sammassimo, S., Mcdonald, A., Arroyo, C. H., Sanchez, J. F., Forcade, E., Castagna, L., Stolzel, F., Sanz, J., Tischer, J., Ciceri, F., Valcarcel, D., Proia, A., Hayden, P. J., Beksac, M., Yakoub-Agha, I., and Schonland, S.

Subjects
medicine.medical_specialty, Platelet Engraftment, Cyclophosphamide, Graft vs Host Disease, Gastroenterology, Bone Marrow, Internal medicine, medicine, Immunology and Allergy, Humans, Cumulative incidence, Multiple myeloma, Retrospective Studies, Hematology, business.industry, hematology, Hematopoietic Stem Cell Transplantation, Cell Biology, medicine.disease, United States, Transplantation, Calcineurin, multiple myeloma, Graft-versus-host disease, surgical procedures, operative, clinical research, Molecular Medicine, Neoplasm Recurrence, Local, business, Unrelated Donors, engraftment, medicine.drug, transplantation
Abstract

Graft-versus-host disease (GVHD) remains among the major causes of treatment failure in patients with multiple myeloma (MM) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). The use of post-transplantation cyclophosphamide (PT-Cy) is now a well-established and widely used method for GVHD prophylaxis after HLA haploidentical HCT. However, the rationale for using PT-Cy in the setting of matched donor transplantation is less apparent, given the lesser degree of bidirectional alloreactivity. In this retrospective study, we investigated the role of PT-Cy as GVHD prophylaxis in patients with multiple myeloma underoing allo-HCT, among different donor types, to determine cumulative incidence of acute and chronic GVHD and impact on engraftment, progression-free survival (PFS), GVHD-free/relapse- free survival (GRFS), overall survival (OS), and NRM A total of 295 patients with MM underwent allo-HCT using grafts from a matched related donor (MRD; n = 67), matched unrelated donor (MUD; n = 72), mismatched related or unrelated donor (MMRD/MMUD, 1 antigen; n = 27), or haploidentical donor (haplo; n = 129) using PT-Cy between 2012 and 2018. In addition to PT-Cy, agents used in GVHD prophylaxis included calcineurin inhibitors in 239 patients (81%), with mycophenolate mofetil in 184 of those 239 (77%). For grade II-IV acute GVHD, the cumulative incidence at day +100 was 30% (95% confidence interval [CI], 25% to 36%), 9% (95% CI, 5% to 12%) for grade III-IV acute GVHD, and 27% (95% CI, 21% to 32%) for chronic GVHD (limited, 21%; extensive, 6%), with no differences by donor type. The median time to neutrophil engraftment was 19d (95% CI, 18-19), with no significant difference by donor type. The median time to platelet engraftment was delayed in haploidentical donor graft recipients (27 days versus 21 days; P < .001). Two-year OS, PFS, GRFS, and NRM were 51% (95% CI, 45% to 58%), 26% (95% CI, 20% to 32%), 24% (95% CI, 18% to 30%), and 19% (95% CI, 14% to 24%), respectively, with no significant difference between different donor types. In multivariable analyses, compared with the haplo donors, the use of MRDs was associated with significantly better OS (hazard ratio [HR], 0.6; 95% CI, 0.38 to 0.95; P = .029), and the use of MUDs was associated with a significantly higher GRFS (HR, 0.63; 95% CI, 0.42 to 0.97; P = .034). There was a trend toward improved PFS with use of MUDs (HR, 0.69; 95% CI, 0.46 to 1.04; P = .08). Our data show that PT-Cy in MM patients undergoing allo-HCT resulted in low rates of acute and chronic GVHD and led to favorable survival, especially in the matched related donor setting. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Published
2021
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15. Graft-versus-host-disease prophylaxis with ATG or PTCY in patients with lymphoproliferative disorders undergoing reduced intensity conditioning regimen HCT from one antigen mismatched unrelated donor.

Author

Paviglianiti A, Ngoya M, Peña M, Boumendil A, Gülbas Z, Ciceri F, Bonifazi F, Russo D, Fegueux N, Stolzel F, Bulabois CE, Socié G, Forcade E, Solano C, Finel H, Robinson S, Glass B, and Montoto S

Subjects
Humans, Female, Male, Middle Aged, Adult, Antilymphocyte Serum therapeutic use, Aged, Transplantation Conditioning methods, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation methods, Cyclophosphamide therapeutic use, Lymphoproliferative Disorders therapy, Lymphoproliferative Disorders mortality, Unrelated Donors
Abstract

Post-transplant cyclophosphamide (PTCY) has been introduced as graft-versus-host disease (GvHD) prophylaxis in mismatched and matched unrelated hematopoietic cell transplant (HCT). However, data comparing outcomes of PTCY or ATG in patients undergoing a 1 antigen mismatched HCT for lymphoproliferative disease are limited. We compared PTCY versus ATG in adult patients with lymphoproliferative disease undergoing a first 9/10 MMUD HCT with a reduced intensity conditioning regimen from 2010 to 2021. Patients receiving PTCY were matched to patients receiving ATG according to: age, disease status at transplant, female to male matching, stem cell source and CMV serology. Grade II-IV acute GvHD at 100 day was 26% and 41% for the ATG and PTCY group, respectively (p = 0.08). Grade III-IV acute GvHD was not significantly different between the two groups. No differences were observed in relapse incidence, non-relapse mortality, progression-free survival, overall survival and GvHD-relapse-free survival at 1 year. The cumulative incidence of 1-year extensive chronic GvHD was 18% in the ATG and 5% in the PTCY group, respectively (p = 0.06). In patients with lymphoproliferative diseases undergoing 9/10 MMUD HCT, PTCY might be a safe option providing similar results to ATG prophylaxis. Due to the limited number of patients, prospective randomized trials are needed., (© 2024. The Author(s).)

Published
2024
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