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Novel Approaches to Prevent Leukemia Relapse Following Allogeneic Hematopoietic Cell Transplantation

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Abstract

Allogeneic hematopoietic cell transplantation is curative for patients with high-risk leukemia, but disease recurrence remains a major cause of treatment failure. New tools are now available to potentially identify patients with minimal residual disease who are at high risk for treatment failure. These improvements in disease detection allow for new opportunities to prevent relapse. The transplant course can be conceptualized into the pretransplant, peritransplant, and posttransplant periods. This article discusses the differing transplant interventions aimed at reducing relapse in each of these periods, focusing on new approaches that are currently being conceived or in early-stage clinical trials.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Davies SM, Wang D, Wang T, et al.: Recent decrease in acute graft-versus-host disease in children with leukemia receiving unrelated donor bone marrow transplants. Biol Blood Marrow Transplant 2009, 15(3):360–366.

    Article  PubMed  Google Scholar 

  2. Eapen M, Raetz E, Zhang MJ, et al.: Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood 2006, 107(12):4961–4967.

    Article  CAS  PubMed  Google Scholar 

  3. MacMillan ML, Davies SM, Nelson GO, et al.: Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant 2008, 14(9 Suppl):16–22.

    Article  PubMed  Google Scholar 

  4. • Bader P, Kreyenberg H, Henze GH, et al.: Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol 2009, 27(3):377–384. This article clearly demonstrates that MRD testing before allo-HCT is feasible and identifies ALL patients at high risk of posttransplant relapse.

    Article  PubMed  Google Scholar 

  5. Jacobsohn DA, Tse WT, Chaleff S, et al.: High WT1 gene expression before haematopoietic stem cell transplant in children with acute myeloid leukaemia predicts poor event-free survival. Br J Haematol 2009, 146(6):669–674.

    Article  CAS  PubMed  Google Scholar 

  6. Bearman SI: The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995, 85(11):3005–3020.

    CAS  PubMed  Google Scholar 

  7. Alderson RF, Kreitman RJ, Chen T, et al.: CAT-8015: a second-generation pseudomonas exotoxin A-based immunotherapy targeting CD22-expressing hematologic malignancies. Clin Cancer Res 2009, 15(3):832–839.

    Article  CAS  PubMed  Google Scholar 

  8. Vallera DA, Todhunter DA, Kuroki DW, et al.: A bispecific recombinant immunotoxin, DT2219, targeting human CD19 and CD22 receptors in a mouse xenograft model of B-cell leukemia/lymphoma. Clin Cancer Res 2005, 11(10):3879–3888.

    Article  CAS  PubMed  Google Scholar 

  9. Lee S, Kim YJ, Min CK, et al.: The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2005, 105(9):3449–3457.

    Article  CAS  PubMed  Google Scholar 

  10. Schultz KR, Bowman WP, Aledo A, et al.: Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children’s Oncology Group study. J Clin Oncol 2009, 27(31):5175–5181.

    Article  CAS  PubMed  Google Scholar 

  11. Burke MJ, Trotz B, Luo X, et al.: Allo-hematopoietic cell transplantation for Ph chromosome-positive ALL: impact of imatinib on relapse and survival. Bone Marrow Transplant 2009, 43(2):107–113.

    Article  CAS  PubMed  Google Scholar 

  12. Burke MJ, Cao Q, Trotz B, et al.: Allogeneic hematopoietic cell transplantation (allogeneic HCT) for treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer 2009, 53(7):1289–1294.

    Article  PubMed  Google Scholar 

  13. • Metzelder S, Wang Y, Wollmer E, et al.: Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 2009, 113(26):6567–6571. These authors demonstrate the activity of sorafenib in chemotherapy-refractory patients with FLT3-ITD AML both before and after allo-HCT.

    Article  CAS  PubMed  Google Scholar 

  14. Schimmer AD, O’Brien S, Kantarjian H, et al.: A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res 2008, 14(24):8295–8301.

    Article  CAS  PubMed  Google Scholar 

  15. Bonapace L, Bornhauser BC, Schmitz M, et al.: Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Invest 2010, 120(4):1310–1323.

    CAS  PubMed  Google Scholar 

  16. Fujii H, Trudeau JD, Teachey DT, et al.: In vivo control of acute lymphoblastic leukemia by immunostimulatory CpG oligonucleotides. Blood 2007, 109(5):2008–2013.

    Article  CAS  PubMed  Google Scholar 

  17. Hui SK, Kapatoes J, Fowler J, et al.: Feasibility study of helical tomotherapy for total body or total marrow irradiation. Med Phys 2005, 32(10):3214–3224.

    Article  PubMed  Google Scholar 

  18. Hui SK, Verneris MR, Higgins P, et al.: Helical tomotherapy targeting total bone marrow—first clinical experience at the University of Minnesota. Acta Oncol 2007, 46(2):250–255.

    Article  PubMed  Google Scholar 

  19. Pagel JM, Appelbaum FR, Eary JF, et al.: 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission. Blood 2006, 107(5):2184–2191.

    Article  CAS  PubMed  Google Scholar 

  20. Pagel JM, Gooley TA, Rajendran J, et al.: Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 2009, 114(27):5444–5453.

    Article  CAS  PubMed  Google Scholar 

  21. Macmillan ML, Wagner JE: Hematopoietic cell transplantation for Fanconi anaemia—when and how? Br J Haematol 2010 Feb 5 (Epub ahead of print).

  22. Kantarjian H, Gandhi V, Cortes J, et al.: Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood 2003, 102(7):2379–2386.

    Article  CAS  PubMed  Google Scholar 

  23. • Verneris MR, Brunstein CG, Barker J, et al.: Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood 2009, 114(9):4293–4299. This study shows that use of two UCB units is associated with lower rates of leukemia relapse. It is speculated that the reduction in relapse is due to increased alloreactivity associated with both immunocompetent UCB units.

    Article  CAS  PubMed  Google Scholar 

  24. Rocha V, Labopin M, Sanz G, et al.: Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 2004, 351(22):2276–2285.

    Article  CAS  PubMed  Google Scholar 

  25. Takahashi S, Ooi J, Tomonari A, et al.: Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen. Blood 2007, 109(3):1322–1330.

    Article  CAS  PubMed  Google Scholar 

  26. Eapen M, Rubinstein P, Zhang MJ, et al.: Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 2007, 369(9577):1947–1954.

    Article  PubMed  Google Scholar 

  27. Laughlin MJ, Eapen M, Rubinstein P, et al.: Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004, 351(22):2265–2275.

    Article  CAS  PubMed  Google Scholar 

  28. Locatelli F, Rocha V, Chastang C, et al.: Factors associated with outcome after cord blood transplantation in children with acute leukemia. Eurocord-Cord Blood Transplant Group. Blood 1999, 93(11):3662–3671.

    CAS  Google Scholar 

  29. Bicigalupo A, Lamparelli T, Gualandi F, et al.: Increased risk of leukemia relapse with high dose cyclosporine after allogeneic marrow transplantation for acute leukemia: 10-year follow-up of a randomized study. Blood 2001, 98(10):3174–3175.

    Article  CAS  PubMed  Google Scholar 

  30. Locatelli F, Zecca M, Rondelli R, et al.: Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial. Blood 2000, 95(5):1572–1579.

    CAS  PubMed  Google Scholar 

  31. Brown VI, Fang J, Alcorn K, et al.: Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A 2003, 100(25):15113–15118.

    Article  CAS  PubMed  Google Scholar 

  32. Pulsipher MA, Wall DA, Grimley M, et al.: A phase I/II study of the safety and efficacy of the addition of sirolimus to tacrolimus/methotrexate graft versus host disease prophylaxis after allogeneic haematopoietic cell transplantation in paediatric acute lymphoblastic leukaemia (ALL). Br J Haematol 2009, 147(5):691–699.

    Article  CAS  PubMed  Google Scholar 

  33. Tacrolimus and methotrexate with or without sirolimus in preventing graft-versus-host disease in young patients undergoing donor stem cell transplant for acute lymphoblastic leukemia in complete remission. Available at http://clinicaltrials.gov/ct2/show/NCT00382109. Accessed April 15, 2010.

  34. Zeiser R, Spyridonidis A, Wasch R, et al.: Evaluation of immunomodulatory treatment based on conventional and lineage-specific chimerism analysis in patients with myeloid malignancies after myeloablative allogeneic hematopoietic cell transplantation. Leukemia 2005, 19(5):814–821.

    Article  CAS  PubMed  Google Scholar 

  35. Schumm M, Feuchtinger T, Pfeiffer M, et al.: Flow cytometry with anti HLA-antibodies: a simple but highly sensitive method for monitoring chimerism and minimal residual disease after HLA-mismatched stem cell transplantation. Bone Marrow Transplant 2007, 39(12):767–773.

    Article  CAS  PubMed  Google Scholar 

  36. • Jabbour E, Giralt S, Kantarjian H, et al.: Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer 2009, 115(9):1899–1905. These authors demonstrate the feasibility of delivering chemotherapy after allo-HCT.

    Article  CAS  PubMed  Google Scholar 

  37. Carpenter PA, Snyder DS, Flowers ME, et al.: Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood 2007, 109(7):2791–2793.

    CAS  PubMed  Google Scholar 

  38. Wassmann B, Pfeifer H, Stadler M, et al.: Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2005, 106(2):458–463.

    Article  CAS  PubMed  Google Scholar 

  39. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al.: Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005, 105(8):3051–3057.

    Article  CAS  PubMed  Google Scholar 

  40. •Rubnitz JE, Inaba H, Ribeiro RC, et al.: NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 2010, 28(6):955–959. The safety and potential efficacy of postchemotherapy NK-cell infusions are demonstrated. A similar approach could be used after allo-HCT to reduce relapse.

    Article  CAS  PubMed  Google Scholar 

  41. Collins RH Jr, Shpilberg O, Drobyski WR, et al.: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997, 15(2):433–444.

    PubMed  Google Scholar 

  42. Soiffer RJ: Donor lymphocyte infusions for acute myeloid leukaemia. Best Pract Res Clin Haematol 2008, 21(3):455–466.

    Article  CAS  PubMed  Google Scholar 

  43. Miller JS, Weisdorf DJ, Burns LJ, et al.: Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood 2007, 110(7):2761–2763.

    Article  CAS  PubMed  Google Scholar 

  44. Ciceri F, Bonini C, Stanghellini MT, et al.: Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial):a non-randomised phase I-II study. Lancet Oncol 2009, 10(5):489–500.

    Article  PubMed  Google Scholar 

  45. Xue X, Huang X, Nodland SE, et al.: Stable gene transfer and expression in cord blood-derived CD34+ hematopoietic stem and progenitor cells by a hyperactive Sleeping Beauty transposon system. Blood 2009, 114(7):1319–1330.

    Article  CAS  PubMed  Google Scholar 

  46. Serrano LM, Pfeiffer T, Olivares S, et al.: Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. Blood 2006, 107(7):2643–2652.

    Article  CAS  PubMed  Google Scholar 

  47. Zhou Q, Bucher C, Munger ME, et al.: Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia. Blood 2009, 114(18):3793–3802.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Pediatric Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota Amplatz Children’s Hospital, MMC 366, 420 Delaware Street SE, Minneapolis, MN, 55455, USA

    Michael R. Verneris & Michael J. Burke

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  1. Michael R. Verneris
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  2. Michael J. Burke
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Correspondence to Michael R. Verneris.

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Verneris, M.R., Burke, M.J. Novel Approaches to Prevent Leukemia Relapse Following Allogeneic Hematopoietic Cell Transplantation. Curr Hematol Malig Rep 5, 157–162 (2010). https://doi.org/10.1007/s11899-010-0051-0

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