Abstract
We analyzed the use of low-dose alemtuzumab in a cohort of 158 consecutive patients who underwent allogeneic PBSC transplantation. Patients with high-risk acute leukemia were prospectively screened for prophylactic donor lymphocyte infusion (pDLI). Lymphocytes were administered repeatedly at low and non-escalating doses (0.5–1 × 106/kg). Low-dose alemtuzumab was effective in prevention of acute GvHD after sibling or well-matched unrelated transplantation, whereas a more intensified approach was needed after mismatched transplantation. The cumulative incidence of chronic moderate/severe chronic-GvHD (cGvHD) was 15.6%. In total, 63 high-risk leukemia patients were eligible for pDLI. Only 1 out of the 39 pDLI recipients relapsed as compared with 7 out of the 24 recipients, who did not receive pDLI due to logistical hurdles. In multivariate analysis, the use of adjuvant lymphocyte therapy was significantly associated with reduced incidence of relapse and improved disease-free survival. In summary, low-dose alemtuzumab confers to a low cGvHD incidence and the administration of pDLIs in this context is very likely to reduce relapse risk in high risk leukemia patients. This is translated in an estimated 5-year probability of GvHD-free and relapse-free survival of 43.3% for the 136 leukemia patients.
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References
Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P et al. Antithymocyte globulin for Graft-Versus-Host Disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood 2001; 98: 2942–2947.
Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE et al. Thymoglobulin prevents chronic Graft-Versus-Host Disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant. 2006; 12: 560–565.
Kottaridis PD, Milligan DW, Chopra R, Chakraverty RK, Chakrabarti S, Robinson S et al. In vivo CAMPATH-1H prevents Graft-Versus-Host Disease following nonmyeloablative stem cell transplantation. Blood 2000; 96: 2419–2425.
Potter VT, Krishnamurthy P, Barber LD, Lim Z, Kenyon M, Ireland RM et al. Long-term outcomes of alemtuzumab-based reduced-intensity conditioned hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myelogenous leukemia secondary to myelodysplastic syndrome. Biol Blood Marrow Transplant 2014; 20: 111–117.
Chakrabarti S, Mackinnon S, Chopra R, Kottaridis PD, Peggs K, O'Gorman P et al. High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. Blood 2002; 99: 4357–4363.
Soiffer RJ, Lerademacher J, Ho V, Kan F, Artz A, Champlin RE et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood 2011; 117: 6963–6970.
Baron F, Labopin M, Blaise D, Lopez-Corral L, Vigouroux S, Craddock C et al. Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2014; 49: 389–396.
Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR et al. Standard Graft-Versus-Host Disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol 2009; 10: 855–864.
Socie G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR et al. Chronic Graft-Versus-Host Disease: long-term results from a randomized trial on Graft-Versus-Host Disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood 2011; 117: 6375–6382.
Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol 2016; 17: 164–173.
Kroger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M et al. Antilymphocyte globulin for prevention of chronic Graft-Versus-Host Disease. N Engl J Med 2016; 374: 43–53.
Schmid C, Labopin M, Nagler A, Bornhäuser M, Finke J, Fassas A et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 2007; 25: 4938–4945.
Spyridonidis A, Liga M, Triantafyllou E, Themeli M, Marangos M, Karakantza M et al. Pharmacokinetics and clinical activity of very low-dose alemtuzumab in transplantation for acute leukemia. Bone Marrow Transplant 2011; 46: 1363–1368.
Liga M, Triantafyllou E, Tiniakou M, Lambropoulou P, Karakantza M, Zoumbos NC et al. High alloreactivity of low-dose prophylactic donor lymphocyte infusion in patients with acute leukemia undergoing allogeneic hematopoietic cell transplantation with an alemtuzumab-containing conditioning regimen. Biol Blood Marrow Transplant 2013; 19: 75–81.
Marks R, Potthoff K, Hahn J, Ihorst G, Bertz H, Spyridonidis A et al. Reduced-toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: particular activity against advanced hematologic malignancies. Blood 2008; 112: 415–425.
Spyridonidis A, Zeiser R, Wasch R, Bertz H, Finke J . Capillary electrophoresis for chimerism monitoring by PCR amplification of microsatellite markers after allogeneic hematopoietic cell transplantation. Clin Transplant 2005; 19: 350–356.
Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 2014; 123: 3664–3671.
Gratwohl A . The EBMT risk score. Bone Marrow Transplant 2012; 47: 749–756.
Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG et al. Composite end point of Graft-Versus-Host Disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 2015; 125: 1333–1338.
Kanda Y . Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2013; 48: 452–458.
Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol 2005; 23: 5074–5087.
Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012; 367: 1487–1496.
Grullich C, Ziegler C, Finke J . Rabbit anti T-lymphocyte globulin induces apoptosis in peripheral blood mononuclear cell compartments and leukemia cells, while hematopoetic stem cells are apoptosis resistant. Biol Blood Marrow Transplant 2009; 15: 173–182.
Chakraverty R, Orti G, Roughton M, Shen J, Fielding A, Kottaridis P et al. Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution. Blood 2010; 116: 3080–3088.
Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.
Furst D, Muller C, Vucinic V, Bunjes D, Herr W, Gramatzki M et al. High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis. Blood 2013; 122: 3220–3229.
Mead AJ, Thomson KJ, Morris EC, Mohamedbhai S, Denovan S, Orti G et al. HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning. Blood 2010; 115: 5147–5153.
de Lima M, Bonamino M, Vasconcelos Z, Colares M, Diamond H, Zalcberg I et al. Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of Graft-Versus-Host Disease. Bone Marrow Transplant 2001; 27: 73–78.
Schaap N, Schattenberg A, Bar B, Preijers F, van de Wiel van Kemenade E, de Witte T . Induction of graft-versus-leukemia to prevent relapse after partially lymphocyte-depleted allogeneic bone marrow transplantation by pre-emptive donor leukocyte infusions. Leukemia 2001; 15: 1339–1346.
Lutz C, Massenkeil G, Nagy M, Neuburger S, Tamm I, Rosen O et al. A pilot study of prophylactic donor lymphocyte infusions to prevent relapse in adult acute lymphoblastic leukemias after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2008; 41: 805–812.
Schmid C, Schleuning M, Tischer J, Holler E, Haude KH, Braess J et al. Early allo-SCT for AML with a complex aberrant karyotype—results from a prospective pilot study. Bone Marrow Transplant 2012; 47: 46–53.
Jedlickova Z, Schmid C, Koenecke C, Hertenstein B, Baurmann H, Schwerdtfeger R et al. Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation. Bone Marrow Transplant 2016; 51: 663–667.
Rettinger E, Willasch AM, Kreyenberg H, Borkhardt A, Holter W, Kremens B et al. Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation. Blood 2011; 118: 5681–5688.
Solomon SR, Sizemore CA, Zhang X, Brown S, Holland HK, Morris LE et al. Preemptive DLI without withdrawal of immunosuppression to promote complete donor T-cell chimerism results in favorable outcomes for high-risk older recipients of alemtuzumab-containing reduced-intensity unrelated donor allogeneic transplant: a prospective phase II trial. Bone Marrow Transplant 2014; 49: 616–621.
Acknowledgements
We acknowledge the nurses, physicians, technicians and data managers for their dedication to the patients. We specially thank our colleagues in hospitals in Greece and Cyprous for patient referral and fruitful collaboration in patient care.
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All authors were immediately involved in patient’s care. ML and KG provided patient data for analysis. PT and AS analyzed data and wrote the manuscript.
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Tsirigotis, P., Liga, M., Gkirkas, K. et al. Low-dose alemtuzumab for GvHD prevention followed by prophylactic donor lymphocyte infusions in high-risk leukemia. Bone Marrow Transplant 52, 445–451 (2017). https://doi.org/10.1038/bmt.2016.272
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DOI: https://doi.org/10.1038/bmt.2016.272