Abstract
To study the effect of early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation (HSCT) on outcome in pediatric ALL, we reviewed 136 consecutive pediatric patients with ALL who received allogeneic HSCT between 1994 and 2005 at the Hospital for Sick Children, Toronto, Canada. Patients with an absolute lymphocyte count (ALC) <0.3 × 109 per liter at day 21 (n=104) had more than five times risk of relapse compared to those with ALC >0.3 × 109 per liter (n=32) (hazard ratio (HR) 5.3; P=0.002) and had inferior 3-year event-free survival, (EFS), 0.42 (95% confidence interval (CI) 0.32, 0.51) compared to 0.66 (95% CI 0.48, 0.82; P=0.02). Similarly, patients with an ALC <0.3 × 109 per liter (n=48) at day 30 were more than twice as likely to relapse compared to those with an ALC >0.3 × 109 per liter (n=88) (HR 2.2; P=0.01) and had an inferior 3-year EFS, 0.30 (95% CI 0.18, 0.45) compared to 0.57 (95% CI 0.46, 0.68; P=0.0001). Interestingly, increasing ALC at days 21 and 30 was not associated with increased incidence of acute or chronic GVHD or transplant-related mortality (TRM). Early lymphocyte recovery post-HSCT is associated with a significant GVL without increase in GVHD.
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References
Barrett AJ, Horowitz MM, Pollock BH, Zhang MJ, Bortin MM, Buchanan GR et al. Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission. N Eng J Med 1994; 331: 1253–1258.
Dopfer R, Henze G, Bender-Gotze C, Ebell W, Ehninger G, Friedrich W et al. Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and secondary relapse therapy according to the BFM-and CoALL-protocols: results of German Cooperative study. Blood 1991; 78: 2780–2784.
Mehta J, Powles R, Treleaven J, Horton C, Meller S, Pinkerton CR et al. Outcome of acute leukemia relapsing afer bone marrow transplantation: utility of second transplants and adoptive immunotherapy. Bone Marrow Transplant 1997; 19: 709–719.
Blau IW, Basara N, Bischoff M, Gunzelmann S, Romer E, Kirsten D et al. Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing after a first transplant. Bone Marrow Transplant 2000; 25: 41–45.
Mehta J, Powles R, Treleaven J, Kulkarni S, Singhal S . Induction of graft-versus-host disease as immunotherapy of leukemia relapsing after allogeneic transplantation: single-center experience of 32 adult patients. Bone Marrow Transplant 1997; 20: 129–135.
Cornelissen JJ, Carston M, Kollman C, King R, Dekker AW, Lowenberg B et al. Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood 2001; 97: 1572–1577.
Remberger M, Mattsson J, Hentschke P, Aschan J, Barkholt L, Svennilson J et al. The graft-versus-leukemia effect in haematopoietic stem cell transplantation using unrelated donors. Bone Marrow Transplant 2002; 30: 761–768.
Powles R, Singhal S, Treleaven J, Kulkarni S, Horton C, Mehta J . Identification of patients who may benefit from prophylactic immunotherapy after bone marrow transplantation for acute myeloid leukemia on the basis of lymphocyte recovery early after transplantation. Blood 1998; 91: 3481–3486.
Kumar S, Chen MG, Gastineau DA, Gertz MA, Inwards DJ, Lacy MQ et al. Effect of slow lymphocyte recovery and type of graft-versus-host disease prophylaxis on relapse after allogeneic bone marrow transplantation for acute myeloid leukemia. Bone Marrow Transplant 2001; 28: 951–956.
Kumar S, Chen MG, Gastineau DA, Gertz MA, Inwards DJ, Lacy MQ et al. Lymphocyte recovery after allogeneic bone marrow transplantation predicts risk of relapse in acute lymphoblastic leukemia. Leukemia 2003; 17: 1865–1870.
Chakrabarti S, Brown J, Guttridge M, Pamphilon DH, Lankester A, Marks DI . Early lymphocyte recovery is an important determinant of outcome following allogeneic transplantation with CD34+selected graft and limited T-cell add back. Bone Marrow Transplant 2003; 32: 23–30.
Kim DH, Kim JG, Sohn SK, Sung WJ, Suh JS, Lee KS et al. Clinical impact of early lymphocyte count after allogeneic stem cell transplantation. Br J Haematol 2004; 125: 217–224.
Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.
Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–2050.
Collins Jr RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor lymphocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–444.
Porter DL, Collins Jr RH, Hardy C, Kernan NA, Drobyski WR, Giralt S et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95: 1214–1221.
Porrata LF, Inwards DJ, Lacy MQ, Markovic SN . Immunomodulation of early engrafted natural killer cells with interleukin-2 and interferon-alpha in autologous stem cell transplantation. Bone Marrow Transplant 2001; 28: 673–680.
Soiffer RJ, Murray C, Gonin R, Ritz J . Effect of low-dose interleukin-2 on disease relapse after T-cell depleted allogeneic bone marrow transplantation. Blood 1994; 84: 964–971.
Drobyski WR, Keever CA, Roth MS, Koethe S, Hanson G, McFadden P et al. Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: efficacy and toxicity of a defined T-cell dose. Blood 1993; 82: 2310–2318.
Bader P, Kreyenberg H, Hoelle W, Dueckers G, Handgretinger R, Lang P et al. Increasing mixed chimerism is an important factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy. J Clin Oncol 2004; 22: 1696–1705.
Pavletic ZS, Joshi SS, Pirruccello SJ, Tarantolo SR, Kollath J, Reed EC et al. Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies. Bone Marrow Transplant 1998; 21: 33–41.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 1974; 18: 295–304.
Atkinson K, Horowitz MM, Gale RP, Lee MB, Rimm AA, Bortin MM . Consensus among bone marrow transplanters for diagnosis, grading and treatment of chronic graft-versus-host disease. Bone Marrow Transplant 1989; 4: 247–254.
Jiang YZ, Barrett AJ, Goldman JM, Mavroudis DA . Association of natural killer cell immune recovery with a graft-versus-leukemia effect independent of graft-versus-host disease following allogeneic bone marrow transplantation. Ann Hematol 1997; 74: 1–6.
Koenecke C, Shaffer J, Alexander SI, Preffer F, Dombkowski D, Saidman SL et al. NK cell recovery, chimerism, function, and recognition in recipients of haploidentical hematopoietic cell transplantation following nonmyeloablative conditioning using a humanized anti-CD2 mAb, medi-507. Exp Hematol 2003; 31: 911–923.
Gassas A, Sung L, Saunders EF, Doyle JJ . Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens. Bone Marrow Transplant 2006; 38: 739–743.
Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979; 300: 1068–1073.
Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989; 73: 1720–1728.
Glass B, Uharek L, Gassmann W, Focks B, Bolouri H, Loeffler H et al. Graft-versus-leukemia activity after bone marrow transplantation does not require graft-versus-host disease. Ann Hematol 1992; 64: 255–259.
Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW et al. Tcell-depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120–2130.
Ault KA, Antin JH, Ginsburg D, Orkin SH, Rappeport JM, Keohan ML et al. Phenotype of recovering lymphoid cell populations after marrow transplantation. J Exp Med 1985; 161: 1483–1502.
Niederwieser D, Gastl G, Rumpold H, Marth C, Kraft D, Huber C . Rapid reappearance of large granular lymphocytes (LGL) with concomitant reconstitution of natural killer (NK) activity after human bone marrow transplantation (BMT). Br J Haematol 1987; 65: 301–305.
Herberman RB, Reynolds CW, Ortaldo JR . Mechanism of cytotoxicity by natural killer (NK) cells. Annu Rev Immunol 1986; 4: 651–680.
Adler A, Chervenick PA, Whiteside TL, Lotzova E, Herberman RB . Interleukin 2 induction of lymphokine-activated killer (LAK) activity in peripheral blood and bone marrow of acute leukemia patients. Feasibility of LAK generation in adult patients with active disease and in remission. Blood 1988; 71: 709–716.
Uharek L, Glass B, Gaska T, Zeiss M, Gassmann W, Loffler H . Natural killer cells as effector cells of graft-versus-leukemia activity in a murine transplantation model. Bone Marrow Transplant 1993; 12 (Suppl 3): S57–S60.
Asai O, Longo DL, Tian ZG, Hornung RL, Taub DD, Ruscetti FW et al. Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. J Clin Invest 1998; 101: 1835–1842.
Lundqvist A, McCoy JP, Samsel L, Childs R . Reduction of GVHD and enhanced anti-tumor effects after adoptive infusion of alloreactive Ly49-mismatched NK-cells from MHC-matched donors. Blood 2007; 109: 3603–3606.
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We are indebted to the patients' families, nursing and medical staff of the BMT unit and our referral centers across Ontario for the provision of excellent patient care and continuing support.
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Ishaqi, M., Afzal, S., Dupuis, A. et al. Early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation is associated with significant graft-versus-leukemia effect without increase in graft-versus-host disease in pediatric acute lymphoblastic leukemia. Bone Marrow Transplant 41, 245–252 (2008). https://doi.org/10.1038/sj.bmt.1705891
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DOI: https://doi.org/10.1038/sj.bmt.1705891
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