Bone Marrow Transplantation (2013) 48, 994–995 & 2013 Macmillan Publishers Limited All rights reserved 0268-3369/13 www.nature.com/bmt

LETTER TO THE EDITOR Azacitidine in the treatment of extramedullary relapse of AML after allogeneic hematopoietic cell transplantation

Bone Marrow Transplantation (2013) 48, 994–995; doi:10.1038/ tolerance and no hematological toxicity. Subsequently, he 2 bmt.2012.256; published online 7 January 2013 received a full dose azacitidine (75 mg/m for 7 days) monthly for five cycles. The patient had an excellent response to azacitidine (Figure 1); some skin nodules started to regress after the first cycle while others stabilized with no new lesions. Furthermore, the response was more noticeable after the third cycle. The right groin Extramedullary relapse of AML after allogeneic hematopoietic SCT 2 2 (HSCT) is rare and less well-defined than systemic disease relapse. mass decreased significantly from 4.2 Â 3.3 cm to 2.1 Â 2cm . In a European Group for Blood and Marrow Transplantation Repeated BM evaluation was always negative. Unfortunately, new (EBMT) study, the incidence of extramedullary relapse after HSCT skin lesions appeared after the fifth cycle and were treated with was as low as 0.65% in AML.1 However, other studies have localized radiotherapy. He recently developed systemic relapse reported an incidence of up to 20% among long-term survivors.1–6 with muscle, lung and liver involvement and passed away from There are no established guidelines for clinical decision making multi-organ failure despite aggressive chemotherapy. pertaining to the treatment of extramedullary relapse after HSCT.7 Common practice entails a combination of localized radiation, Patient no. 2 systemic chemotherapy, immunotherapy with donor lymphocyte infusions (DLI), and repeated transplantation if possible. We A 39-year-old female known to have AML-M2 diagnosed in 1992 present in this report our experience in treating two patients with underwent allogeneic HSCT in April 2000 in third CR. Conditioning extramedullary non-hematological disease in the setting of consisted of high-dose CY and 8 Gy TBI. She did not develop any relapsed AML previously treated with HSCT, DLI, chemotherapy GVHD. She presented in July 2010 with gingival hypertrophy. and radiotherapy. Biopsy was consistent with myeloid sarcoma. BM examination showed no increase in blasts. Both BM and gingival karyotypes were complex and predominantly of patient origin. The patient received two cycles of fludarabine, high-dose cytarabine and Patient no. 1 G-CSF (FLAG regimen) with low-dose gemtuzumab ozogamycin A 34-year-old man presented with diffuse maculopapular rash (3 mg/m2). After the first cycle, she had a rapid but transient with multiple erythematous skin nodules. BM studies were resolution of her gingival hypertrophy. BM examination after the negative. Skin biopsy was consistent with monoblastic leukemia second cycle was negative for leukemia, karyotype was of donor cutis. He received induction with idarubicin/cytarabine in Decem- origin (46, XY), and chimerism was 100% donor. Gingival ber 2010 with disappearance of all skin lesions and negative skin hypertrophy did not improve, and it even increased after biopsy. He then received the first consolidation (idarubicin/ additional treatment with FLAG and DLI. She was started in April cytarabine) followed by allogeneic HSCT in February 2011 with a 2011 on azacitidine 75 mg/m2/day for 7 days every 28 days. She preparative regimen of fludarabine, busulfan and thymoglobulin. had a gradual response, and after the 4th cycle the gingival He achieved full donor chimerism at Days 30 and 100, with no hypertrophy significantly decreased in size, with almost complete evidence of GVHD. Five months after transplantation, he devel- resolution after the 8th cycle (Figure 2). Thus, she was maintained oped three small skin nodules, the biopsy of which confirmed on azacitidine with negative BM evaluation every 3 months. She early relapse. He received salvage chemotherapy with cladribine, has received her 17th dose of azacitidine in August 2012 and she high-dose cytarabine and G-CSF (CLAG regimen) in August 2011 is doing well with normal life activities and small stable gingival followed by DLI (1.0 Â 107 cells/kg) as well as local radiotherapy. lesion. Unfortunately, new skin lesions rapidly reappeared at other sites. Extramedullary relapse after HSCT in AML is rare with a median In addition, the patient developed a right s.c. groin mass of time to diagnosis longer than to BM relapse (about 12–17 months 3 Â 2cm2 that was positive for myeloid leukemia with no other vs 3–6 months, respectively).1,3,6 Although the prognosis is poor evidence of systemic disease by computed tomography (CT) scan for extramedullary relapse, it is better than for systemic relapse, and BM evaluation. The patient was started on a reduced dose of with a 2-year OS of 11–38%.1,3 Therefore, the goal of therapy azacitidine (32 mg/m2 for 5 days) in February 2012 with good should be to prevent systemic relapse.

Figure 1. Regression of the skin lesion after treatment with 5-azacitidine: right leg erythematous, skin nodule (leukemia cutis) before starting azacitidine (a). The lesion became more flat and less erythematous and smaller after the second cycle (b). Complete resolution of the nodule with residual dark discoloration of the skin after the fifth cycle (c). Letter to the Editor 995

Figure 2. Regression of gingival hypertrophy (myeloid sarcoma) after treatment with 5-azacitidine: gingival hypertrophy before starting azacitidine (a), mild response after three cycles (b), almost complete resolution of gingival hypertrophy after eight cycles (c), no clinical evidence of disease after the 15th cycle of azacitidine (d).

The DNA hypomethylating agent 5-azacitidine has been studied 4Department of Dermatology, Tenon Hospital, APHP and Paris 6 in patients with AML/MDS post allogeneic HSCT as maintenance University, Paris, France and therapy, salvage therapy and as treatment of imminent relapse. 5Hematologie Clinique, Universite´ de Nantes and INSERM CRNCA De Lima et al.8 showed that maintenance azacitidine at 32 mg/m2/ UMR892, Nantes, France day for 5 days was safe and could be administered after allogeneic E-mail: [email protected] transplant for at least four cycles to heavily pretreated AML/MDS 6These authors contributed equally to this work. patients. This treatment may prolong event-free and OS, and more cycles may be associated with greater benefit. Platzbecker et al.9 demonstrated that minimal residual disease-triggered treatment with azacitidine appears to be an effective strategy for preventing REFERENCES or substantially delaying hematologic relapse with an acceptable 1 Bekassy AN, Hermans J, Gorin NC, Gratwohl A. Granulocytic sarcoma after allo- safety profile in patients with MDS or AML after HSCT. Serrao geneic bone marrow transplantation: a retrospective European multicenter sur- et al.10 have recently reported on a 62-year-old man with CMML vey. Acute and Chronic Leukemia Working Parties of the European Group for who developed an isolated bone lesion in the humerus as the only Blood and Marrow Transplantation. Bone Marrow Transplant 1996; 17: 801–808. extramedullary localization of his disease.10 The patient was 2 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 treated successfully with azacitidine and radiotherapy. recurring acute leukemia. Leukemia 1998; 12: 1676–1681. To the best of our knowledge, our two cases are the first 3 Cunningham I. Extramedullary sites of leukemia relapse after transplant. reported cases that showed a very good response to 5-azacitidine Leuk Lymphoma 2006; 47: 1754–1767. in the setting of extramedullary AML after failure of allogeneic 4 Frassoni F, Barrett AJ, Granena A, Ernst P, Garthon G, Kolb HJ et al. Relapse after HSCT, DLI, radiotherapy and chemotherapy. The two patients allogeneic bone marrow transplantation for acute leukaemia: a survey by the responded to azacitidine with no BM relapse; one relapsed and E.B.M.T. of 117 cases. Br J Haematol 1988; 70: 317–320. passed away and the other is maintained on azacitidine with 5 Koc Y, Miller KB, Schenkein DP, Daoust P, Sprague K, Berkman E. Extramedullary normal performance. These results suggest that 5-azacitidine is tumors of myeloid blasts in adults as a pattern of relapse following allogeneic effective in inducing responses in the setting of extramedullary bone marrow transplantation. Cancer 1999; 85: 608–615. relapse of AML after failure of all treatment modalities including 6 LeeKH,LeeJH,ChoiSJ,KimS,SeolM,LeeYSet al. Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk allogeneic HSCT. Our findings warrant further evaluation in the factors and clinical course. Bone Marrow Transplant 2003; 32: 835–842. context of prospective clinical studies. 7 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. CONFLICT OF INTEREST 8 de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K et al. The authors declare no conflict of interest. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or A Antar1,6, ZK Otrock2,6, M Kharfan-Dabaja3, Z Salem1, S Aractingi4, myelodysplastic syndrome: a dose and schedule finding study. Cancer 2010; 116: M Mohty5 and A Bazarbachi1 5420–5431. 1Department of Internal Medicine, American University of Beirut 9 Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after Medical Center, Beirut, Lebanon; 2 allogeneic HSCT: results of the RELAZA trial. Leukemia 2012; 26: 381–389. Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, 10 Serrao A, Loglisci G, Salaroli A, Zacheo I, Alimena G, Breccia M. Azacitidine Cleveland, OH, USA; followed by radiotherapy as effective treatment for chronic myelomonocytic 3 Department of Blood and Marrow Transplantation, Moffitt Cancer leukemia with extramedullary localization. Leuk Lymphoma (e-pub ahead of print Center, Tampa, FL, USA; 9 July 2012).

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