Abstract
Extramedullary (EM) relapse of leukemia after allo-SCT in patients with AML/myelodysplastic syndrome has been increasingly reported. The reduced effectiveness of the GVL effect in EM sites, as compared with BM, has been suggested to underlie this problem. We retrospectively analyzed the pattern of relapse after haploidentical SCT (haplo-SCT), performed as the first or second SCT. Among 38 patients who received haplo-SCT as their first SCT, the cumulative incidences of BM and EM relapse at 3 years were 40.5 and 10.9%, respectively. Among 19 patients who received haplo-SCT as their second SCT, the cumulative incidences of BM and EM relapse were 30.9 and 31.9%, respectively. Moreover, most of the patients who underwent repeat haplo-SCT for the treatment of EM relapse had further EM relapse at other sites. Post-relapse survival did not differ significantly with different patterns of relapse. The frequent occurrence of EM relapse after haplo-SCT, particularly when performed as a second SCT, suggests that the potent GVL effect elicited by an HLA disparity also occurs preferentially in BM. Our findings emphasize the need for a treatment strategy for EM relapse that recognizes the reduced susceptibility of EM relapse to the GVL effect.
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References
Clark WB, Strickland SA, Barrett AJ, Savani BN . Extramedullary relapses after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome. Haematologica 2010; 95: 860–863.
Bekassy AN, Hermans J, Gorin NC, Gratwohl A . Granulocytic sarcoma after allogeneic bone marrow transplantation: a retrospective European multicenter survey. Acute and Chronic Leukemia Working Parties of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1996; 17: 801–808.
Chong G, Byrnes G, Szer J, Grigg A . Extramedullary relapse after allogeneic bone marrow transplantation for haematological malignancy. Bone Marrow Transplant 2000; 26: 1011–1015.
Lee KH, Lee JH, Choi SJ, Kim S, Seol M, Lee YS et al. Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course. Bone Marrow Transplant 2003; 32: 835–842.
Choi SJ, Lee JH, Kim S, Seol M, Lee YS, Lee JS et al. Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse. Leukemia 2004; 18: 1789–1797.
Takami A, Okumura H, Yamazaki H, Kami M, Kim SW, Asakura H et al. Prospective trial of high-dose chemotherapy followed by infusions of peripheral blood stem cells and dose-escalated donor lymphocytes for relapsed leukemia after allogeneic stem cell transplantation. Int J Hematol 2005; 82: 449–455.
Anasetti C, Beatty PG, Storb R, Martin PJ, Mori M, Sanders JE et al. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol 1990; 29: 79–91.
Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, Inoko H et al. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program. N Engl J Med 1998; 339: 1177–1185.
Kanda Y, Chiba S, Hirai H, Sakamaki H, Iseki T, Kodera Y et al. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991–2000). Blood 2003; 102: 1541–1547.
Ogawa H, Ikegame K, Kawakami M, Tsuboi A, Kim EH, Hosen N et al. Powerful graft-versus-leukemia effects exerted by HLA-haploidentical grafts engrafted with a reduced-intensity regimen for relapse following myeloablative HLA-matched transplantation. Transplantation 2004; 78: 488–489.
Ogawa H, Ikegame K, Yoshihara S, Kawakami M, Fujioka T, Masuda T et al. Unmanipulated HLA 2–3 antigen-mismatched (haploidentical) stem cell transplantation using nonmyeloablative conditioning. Biol Blood Marrow Transplant 2006; 12: 1073–1084.
Ogawa H, Ikegame K, Kaida K, Yoshihara S, Fujioka T, Taniguchi Y et al. Unmanipulated HLA 2–3 antigen-mismatched (haploidentical) bone marrow transplantation using only pharmacological GVHD prophylaxis. Exp Hematol 2008; 36: 1–8.
Huang XJ, Chang YJ . Unmanipulated HLA-mismatched/haploidentical blood and marrow hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011; 17: 197–204.
Hu YX, Cui Q, Liang B, Huang H . Relapsing hematologic malignancies after haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011; 17: 1099–1111.
Ogawa H, Tamaki H, Ikegame K, Soma T, Kawakami M, Tsuboi A et al. The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood 2003; 101: 1698–1704.
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075–4083.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.
Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.
Lee KH, Lee JH, Kim S, Lee JS, Kim SH, Kim WK . High frequency of extramedullary relapse of acute leukemia after allogeneic bone marrow transplantation. Bone Marrow Transplant 2000; 26: 147–152.
Lee JH, Choi SJ, Seol M, Lee YS, Ryu SG, Park CJ et al. Anti-leukemic effect of graft-versus-host disease on bone marrow and extramedullary relapses in acute leukemia. Haematologica 2005; 90: 1380–1388.
Jiang YZ, Cullis JO, Kanfer EJ, Goldman JM, Barrett AJ . T cell and NK cell mediated graft-versus-leukaemia reactivity following donor buffy coat transfusion to treat relapse after marrow transplantation for chronic myeloid leukaemia. Bone Marrow Transplant 1993; 11: 133–138.
Berthou C, Leglise MC, Herry A, Balcon D, Hardy E, Lessard M et al. Extramedullary relapse after favorable molecular response to donor leukocyte infusions for recurring acute leukemia. Leukemia 1998; 12: 1676–1681.
Chakraverty R, Cote D, Buchli J, Cotter P, Hsu R, Zhao G et al. An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. J Exp Med 2006; 203: 2021–2031.
Tallman MS, Hakimian D, Shaw JM, Lissner GS, Russell EJ, Variakojis D . Granulocytic sarcoma is associated with the 8;21 translocation in acute myeloid leukemia. J Clin Oncol 1993; 11: 690–697.
Zhang XH, Zhang R, Li Y . Granulocytic sarcoma of abdomen in acute myeloid leukemia patient with inv(16) and t(6;17) abnormal chromosome: case report and review of literature. Leuk Res 2010; 34: 958–961.
Park KU, Lee DS, Lee HS, Kim CJ, Cho HI . Granulocytic sarcoma in MLL-positive infant acute myelogenous leukemia: fluorescence in situ hybridization study of childhood acute myelogenous leukemia for detecting MLL rearrangement. Am J Pathol 2001; 159: 2011–2016.
Byrd JC, Weiss RB, Arthur DC, Lawrence D, Baer MR, Davey F et al. Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol 1997; 15: 466–475.
Savani BN, Mielke S, Reddy N, Goodman S, Jagasia M, Rezvani K . Management of relapse after allo-SCT for AML and the role of second transplantation. Bone Marrow Transplant 2009; 44: 769–777.
Ando T, Mitani N, Matsui K, Yamashita K, Nomiyama J, Tsuru M et al. Recurrent extramedullary relapse of acute myelogenous leukemia after allogeneic hematopoietic stem cell transplantation in a patient with the chromosomal abnormality t(8;21) and CD56-positivity. Int J Hematol 2009; 90: 374–377.
Koc Y, Miller KB, Schenkein DP, Daoust P, Sprague K, Berkman E . Extramedullary tumors of myeloid blasts in adults as a pattern of relapse following allogeneic bone marrow transplantation. Cancer 1999; 85: 608–615.
Owonikoko T, Agha M, Balassanian R, Smith R, Raptis A . Gemtuzumab therapy for isolated extramedullary AML relapse following allogeneic stem-cell transplant. Nat Clin Pract Oncol 2007; 4: 491–495.
Ando T, Mitani N, Matsunaga K, Nakazora T, Gondo T, Yujiri T et al. Gemtuzumab ozogamicin therapy for isolated extramedullary AML relapse after allogeneic hematopoietic stem-cell transplantation. Tohoku J Exp Med 2010; 220: 121–126.
Karlin L, Itti E, Pautas C, Rachid M, Bories D, Cordonnier C et al. PET-imaging as a useful tool for early detection of the relapse site in the management of primary myeloid sarcoma. Haematologica 2006; 91 (12 Suppl): ECR54.
Mantzarides M, Bonardel G, Fagot T, Gontier E, Soret M, Revel TD et al. Granulocytic sarcomas evaluated with F-18-fluorodeoxyglucose PET. Clin Nucl Med 2008; 33: 115–117.
Rao S, Langston A, Galt JR, Halkar RK . Extramedullary acute myeloid leukemia and the use of FDG-PET/CT. Clin Nucl Med 2009; 34: 365–366.
Suga K, Kawakami Y, Hiyama A, Takeda K, Tanizawa Y, Matsunaga N . F-18 FDG PET/CT findings in a case of gastric relapse of acute myeloblastic leukemia. Clin Nucl Med 2009; 34: 788–790.
Acknowledgements
We thank the medical, nursing, and laboratory staff for their contributions to this study. We are also grateful to Ms Aya Yano and Ms Kimiko Yamamoto for their technical assistance and to Ms Saori Hatemura, Mr Shigeo Kimura, Ms Kazuko Saida, and Ms Kumiko Sugawara for their assistance with data collection. This study was supported in part by a grant from the Japanese Ministry of Health, Labor and Welfare.
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Yoshihara, S., Ikegame, K., Kaida, K. et al. Incidence of extramedullary relapse after haploidentical SCT for advanced AML/myelodysplastic syndrome. Bone Marrow Transplant 47, 669–676 (2012). https://doi.org/10.1038/bmt.2011.163
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DOI: https://doi.org/10.1038/bmt.2011.163
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