Total body irradiation dose escalation decreases risk of progression and graft rejection after hematopoietic cell transplantation for myelodysplastic syndromes or myeloproliferative neoplasms

Federico Monaco, Bart L Scott, Thomas R Chauncey, Finn B Petersen, Barry E Storer, Frederic Baron, Mary E Flowers, H Joachim Deeg, David G Maloney, Rainer Storb, Brenda M Sandmaier, Federico Monaco, Bart L Scott, Thomas R Chauncey, Finn B Petersen, Barry E Storer, Frederic Baron, Mary E Flowers, H Joachim Deeg, David G Maloney, Rainer Storb, Brenda M Sandmaier

Abstract

A non-myeloablative regimen of fludarabine and 200 cGy total body irradiation combined with post-grafting immunosuppression with mycophenolate mofetil and a calcineurin inhibitor facilitates allogeneic hematopoietic cell transplantation from HLA-matched related or unrelated donors in older patients and/or those with comorbidities. However, outcomes of prior studies have been disappointing in patients with myelodysplastic syndromes or myeloproliferative neoplasms due to high incidences of progression or graft failure (together termed hematopoietic cell transplantation-failure). We hypothesized that escalating the total body irradiation dose may improve the outcomes and subsequently performed a phase II total body irradiation dose-escalation trial. Patients with median age 66 years were enrolled in two arms to receive non-myeloablative conditioning followed by hematopoietic cell transplantation with total body irradiation dose escalation for excessive hematopoietic cell transplantation-failure: Arm A: myeloproliferative neoplasm/myelodysplastic syndrome low risk (n=36); and Arm B: myelodysplastic syndrome high-risk/chronic myelomonocytic leukemia (n=41). Total body irradiation dose levels were: Level-1 (300 cGy), Level-2 (400 cGy), or Level-3 (450 cGy). Patients received intravenous fludarabine 30 mg/m2 for three days. Total body irradiation was administered on day 0 followed by infusion of peripheral blood stem cells from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with mycophenolate mofetil and cyclosporine was administered. The primary end point was day 200 hematopoietic cell transplant failure, with the objective of reducing the incidence to <20%. The primary end point was reached on Arm A at dose Level-1 (300 cGy total body irradiation) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 11%, and on Arm B at dose Level-3 (450 cGy) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 9%. Increasing the total body irradiation dose leads to a higher success rate with non-myeloablative conditioning by reducing relapse and rejection. Further studies are necessary to decrease non-relapse mortality, especially among patients with high-risk disease. Trial registered under clinicaltrials.gov identifier: NCT00397813.

Copyright© 2019 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Flow diagram of the progress through the phases of the study. MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm; PNH: paroxysmal nocturnal hemoglobinuria; CMML: chronic myelomonocytic leukemia; TBI: total body irradiation; cGy: centigray; n: number.
Figure 2.
Figure 2.
Outline of treatment plan involving conditioning regimens and graft-versus-host disease (GvHD) prophylaxis. FLU: fludarabine; TBI: total body irradiation; HCT: hematopoietic cell transplantation; MRD: HLA-matched related donor; URD: HLA-matched unrelated donor; MMF: mycophenolate mofetil; CSP: cyclosporine; cGy: centigray; hrs: hours.
Figure 3.
Figure 3.
Patients enrolled in Arm A receiving 300 cGy total body irradiation (TBI) and patients enrolled in Arm B receiving 450 cGy TBI had reduced day 200 hematopoietic cell transplantation (HCT) failure. Transplant outcomes by Arm and TBI dose: (A) HCT-failure, (B) overall survival, (C) progression-free survival (PFS), (D) non-relapse mortality (NRM), and (E) relapse incidence.
Figure 4.
Figure 4.
Incidences of graft-versus-host disease (GvHD) were comparable between different Arms and TBI doses. (A) Acute GvHD, (B) chronic GvHD.

References

    1. Scott B, Deeg HJ. Hemopoietic cell transplantation as curative therapy of myelodysplastic syndromes and myeloproliferative disorders. Best Pract Res Clin Haematol. 2006;19(3):519–522.
    1. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97(11):3390–3400.
    1. Niederwieser D, Maris M, Shizuru JA, et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and post-grafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood. 2003;101(4):1620–1629.
    1. Maris MB, Niederwieser D, Sandmaier BM, et al. HLA-matched unrelated donor hematopoietic cell transplantation after non-myeloablative conditioning for patients with hematologic malignancies. Blood. 2003;102(6):2021–2030.
    1. Sandmaier BM, Maris M, Maloney DG, et al. Low-dose total body irradiation (TBI) conditioning for hematopoietic cell transplants (HCT) from HLA-matched related (MRD) and unrelated (URD) donors for patients with hematologic malignancies: a five-year experience. Blood. 2003; 102(11):78–79.
    1. Baron F, Maris MB, Sandmaier BM, et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning. J Clin Oncol. 2005;23(9):1993–2003.
    1. Copelan E, Casper JT, Carter SL, et al. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007; 13(12):1469–1476.
    1. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18(4):295–304.
    1. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18(6):695–706.
    1. Scott BL, Sandmaier BM, Storer B, et al. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia. 2006;20(1):128–135.
    1. Laport GG, Sandmaier BM, Storer BE, et al. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant. 2008;14(2):246–255.
    1. Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimens. Blood. 1990; 76(9):1867–1871.
    1. Storb R, Yu C, Wagner JL, et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997;89(8): 3048–3054.
    1. Hogan WJ, Little MT, Zellmer E, et al. Postgrafting immunosuppression with sirolimus and cyclosporine facilitates stable mixed hematopoietic chimerism in dogs given sublethal total body irradiation before marrow transplantation from DLA-identical littermates. Biol Blood Marrow Transplant. 2003;9(8):489–495.
    1. Storb R, Raff RF, Appelbaum FR, et al. Comparison of fractionated to single-dose total body irradiation in conditioning canine littermates for DLA-identical marrow grafts. Blood. 1989;74(3):1139–1143.
    1. Storb R, Raff RF, Appelbaum FR, et al. Fractionated versus single-dose total body irradiation at low and high dose rates to condition canine littermates for DLA-identical marrow grafts. Blood. 1994;83(11): 3384–3389.
    1. Stelljes M, Bornhauser M, Kroger M, et al. Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood. 2005; 106(9):3314–3321.
    1. Appelbaum FR, Brown P, Sandmaier B, et al. Antibody-radionuclide conjugates as part of a myeloblative preparative regimen for marrow transplantation. Blood. 1989; 73(8):2202–2208.
    1. Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after conditioning with 131 I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syn drome. Blood. 2009;114(27):5444–5453.
    1. Gopal AK, Guthrie KA, Rajendran J, et al. 90 Y-Ibritumomab tiuxetan, fludarabine, and TBI-based nonmyeloablative allogeneic transplantation conditioning for patients with persistent high-risk B-cell lymphoma. Blood. 2011;118(4):1132–1139.
    1. Sandmaier BM, Bethge WA, Wilbur DS, et al. Bismuth 213-labeled anti-CD45 radioim-munoconjugate to condition dogs for non-myeloablative allogeneic marrow grafts. Blood. 2002;100(1):318–326.
    1. Chen Y, Kornblit B, Hamlin DK, et al. Durable donor engraftment after radioim-munotherapy using alpha-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation. Blood. 2012;119(5):1130–1138.
    1. Nakamae H, Wilbur DS, Hamlin DK, et al. Biodistribution, myelosuppression, and toxicities in mice treated with an anti-CD45 antibody labeled with the α-emitting radionuclides bismuth-213 or astatine-211. Cancer Res. 2009;69(6):2408–2415.
    1. Kornblit B, Maloney DG, Storer BE, et al. A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation. Haematologica. 2014; 99(10): 1624–1631.
    1. Sandmaier BM, Maloney DG, Storer BE, et al. Sirolimus combined with mycophenolate mofetil (MMF) and cyclosporine (CSP) significantly improves prevention of acute graft-versus-host-disease (GVHD) after unrelated hematopoietic cell transplantation (HCT): Results from a phase III randomized multi-center trial. Blood. 2016;128(22):506.
    1. Lim Z, Brand R, Martino R, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol. 2010; 28(3):405–411.
    1. McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010;28(11):1878–1887.
    1. Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2017;35(11):1154–1161.
    1. Storb R, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation. Haematologica. 2016;101(5):521–530.

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