CLINICAL AND LABORATORY OBSERVATIONS
Azacitidine in the Treatment of Pediatric Therapy-related Myelodysplastic Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation
Akiko Inoue, MD, PhD, Chihiro Kawakami, MD, PhD, Kimitaka Takitani, MD, PhD, and Hiroshi Tamai, MD, PhD
recent results of studies of low-dose AZA as maintenance Summary: We herein present a case of pediatric therapy-related or salvage therapy in higher-risk MDS and AML patients myelodysplastic syndrome (t-MDS) with complex karyotype who after allogeneic HSCT indicated that AZA is well tolerated was treated with azacitidine (AZA) for AML1-EVI1 fusion tran- and associated with a prolonged progression-free and script as minimal residual disease after allogeneic hematopoietic overall survival.4,5 stem cell transplantation (HSCT). The patient was started on AZA 41 days after the HSCT without having achieved complete remis- This report presents the case of a child with t-MDS sion. After 9 cycles of AZA, the AML1-EVI1 fusion transcript who received AZA to treat and prevent disease recurrence disappeared, and there was no manifestation of graft versus host after allogeneic HSCT. disease during AZA treatment. Preemptive AZA treatment for minimal residual disease has an acceptable safety profile and appears to be an effective strategy for preventing or substantially CASE REPORT delaying hematological relapse in pediatric patients with high-risk An 11-year-old male was found to have a bleeding tendency. He myelodysplastic syndrome after HSCT. had previously been diagnosed with medulloblastoma of the cer- ebellum at 1 year. After the gross total resection of the tumor, he had Key Words: therapy-related myelodysplastic syndrome, azacitidine, received chemotherapy for 6 months. The total doses of chemotherapy allogeneic transplantation, AML1-EVI1 with cyclophosphamide, cisplatin, etoposide, vincristine, thiotepa, and melphalan were 12 g/m2,360mg/m2,2g/m2,15mg/m2,26mg/kg,and (J Pediatr Hematol Oncol 2014;36:e322–e324) 6 mg/kg, respectively. Furthermore, when he was 7 years old, he had been diagnosed with osteosarcoma of the right tibia. He had received chemotherapy for 1 year, and underwent gross total resection of the osteosarcoma. The total doses of chemotherapy using cisplatin, dox- herapy-related myelodysplastic syndrome or acute orubicin, methotrexate, ifosfamide, and pirarubicine during that period Tmyeloid leukemia (t-MDS/AML) is a well-recognized were 500 mg/m2,180mg/m2, 216 g/m2,36g/m2, and 585 mg/m2, complication of cancer treatment. The major factors respectively. He had maintained a CR for both of cancers with sub- contributing to t-MDS/AML are exposure to alkylating clinical cardiac dysfunction and cisplatin-induced hearing loss as a late agents, epipodophyllotoxin, and radiation therapy. Patients effect. He was affected by 3 malignancies, but he had no family history with t-MDS/AML generally have an inferior outcome of cancer which is associated with Li-Fraumeni syndrome. We have because of the more progressive clinical course compared not checked the TP53 germline mutation. with patients with de novo disease, with a lower complete The initial laboratory findings revealed pancytopenia; a white 1,2 blood cell count of 1940/mL with 0.5% blasts, 11.1 g/dL hemo- remission (CR) rate and a shorter duration of CR. globin, and a platelet count of 36,000/mL in the peripheral blood. Accumulated data indicate that the clinical and sub- The bone marrow (BM) examination showed infiltration of 17.1% clinical organ toxicities due to prior cancer therapy are also blast cells with dysplasia in megakaryocytes and the presence of risk factors that limit the success of subsequent therapy. clusters of CD34-positive precursor cells, and also revealed hypo- Allogeneic hematopoietic stem cell transplantation (HSCT) is plastic and fibrous BM. An immunophenotypic analysis disclosed a potential curative treatment for t-MDS/AML. Nevertheless, that the cells were positive for CD4, CD7, CD13, CD33, CD34, in patients eligible to undergo allogeneic HSCT, disease relapse CD117, and HLA-DR. The patient was diagnosed with t-MDS still remains a major cause of treatment failure. (RAEB2). Twenty metaphase cells revealed a karyotype of 45,XY, Azacitidine (AZA), a hypomethylating agent, is the t(3;21)(q26.2;q22), À7 [8], 46 idem, +8 [7], 46,XY [5]. Fluo- rescence in situ hybridization (FISH) demonstrated monosomy 7 first drug that has shown a significant survival advantage and trisomy 8, and an AML1/EVI1 gene translocation was detected compared with conventional care regimens in patients with by reverse transcription-PCR (RT-PCR). higher-risk MDS. The effect of AZA in t-MDS/AML is not Because of the cardiotoxicity of anthracyclines and hypo- established, but the recent report showed that by compar- plastic marrow, AML-type induction chemotherapy was predicted ison with de novo MDS/AML received AZA for at least 1 to be poorly tolerated, so he started chemotherapy with low-dose cycle (median 4 cycles), t-MDS/AML had a similar cytarabine (AraC) alone; 7 doses of 50 mg/m2 were administered response rate (38% vs. 45% in de novo MDS/AML).3 The (Fig. 1). However, he did not respond, so the AraC was changed to AZA. A second round of chemotherapy using 7 doses of 75 mg/m2 was administered without complications. This treatment was not Received for publication June 8, 2013; accepted August 29, 2013. effective too, that is, trasfusion dependency was maintained and From the Department of Pediatrics, Osaka Medical College, Takatsuki, the BM examination showed infiltration of >80% monosomy 7 or Osaka, Japan. trisomy 8 cells (FISH). The authors declare no conflict of interest. Reprints: Akiko Inoue, MD, PhD, Department of Pediatrics, Osaka Therefore, the patient underwent allogeneic peripheral blood Medical College, 2-7, Daigakumachi, Takatsuki, Osaka 569-8686, stem cell transplantation from a HLA-matched sibling at 2 months Japan (e-mail: [email protected]). after the diagnosis without having achieved a CR. The conditioning Copyright r 2014 by Lippincott Williams & Wilkins regimen was busulfan; 3.2 mg/kg on days À7toÀ6, and e322 | www.jpho-online.com J Pediatr Hematol Oncol Volume 36, Number 5, July 2014 J Pediatr Hematol Oncol Volume 36, Number 5, July 2014 Azacitidine After Allogeneic Transplantation
FIGURE 1. Clinical course. AraC indicates cytarabine; AZA, azacitidine; BU, busulfan; CsA, cyclosporine; Flu, fludarabine; L-PAM, melphalan; PBSCT, peripheral blood stem cell transplantation; PC, platelet concentrates; RCC, red cell concentrates.
fludarabine; 30 mg/m2 on days À5toÀ2, and melphalan; 70 mg/m2 4 patients had t-AML, and 1 patient had de novo AML). They on days À3toÀ2, and the graft versus host disease (GVHD) pro- described that MDS/AML associated with t(3;21)(q26.2;q22) phylaxis was performed using cyclosporine alone. Engraftment was usually showed marked multilineage dysplasia and frequent achieved on day 10, and acute GVHD (skin grade II) was observed. A association with À7 and a complex karyotype, furthermore, CR and complete donor chimerism were obtained in the BM, and all 17 patients died with 1- and 2-year survival rates of 35% monosomy 7 and trisomy 8 were no longer detected by FISH, but an 7 AML1/EVI1 fusion transcript was detected by RT-PCR. and 6%, respectively. Forty-one days after the peripheral blood stem cell trans- Chromosome 3q26.2 abnormalities have been shown plantation, the patient was started on low-dose AZA subcutaneously; to activate EVI1 expression. EVI1 plays an important role 5 doses of 32 mg/m2 after withdrawal of cyclosporine, based on recent in pathogenesis by promoting myeloid proliferation and reports.3,4 After 3 cycles of low-dose AZA every 4 weeks, there was blocking differentiation. Vazquez et al8 have confirmed that no hematological toxicity, and a CR had been maintained, but an EVI1 overexpression is an adverse prognostic factor in AML1/EVI1 fusion transcript was still detected by RT-PCR. There- AML patients and the total absence of EVI1 expression 2 fore, the patient received a higher dose of AZA; 5 doses of 75 mg/m might have a prognostic impact on the outcome of AML every 4 weeks from the fourth to ninth cycles. Reversible grade1 patients, and that this pattern may be regulated by epi- neutropenia occurred, rather, platelets increased gradually. After the ninth cycle of AZA, the AML1/EVI1 fusion tran- genetic mechanisms involving DNA methylation. script in the BM disappeared, and AZA was discontinued. During Previous clinical studies in patients with MDS and AZA treatment, there were no manifestations of GVHD. The AML after allogeneic HSCT have shown that low doses of patient is now doing well, and has been free from recurrence for AZA (8 to 40 mg/m2/d for 5 d every 4 wk) as salvage or over 26 months after the HSCT. maintenance therapy could be a potential treatment option to prevent or delay hematological relapse.4,5 So we herein presented a case of pediatric t-MDS with DISCUSSION À7/ + 8/ t(3;21)(q26.2;q22) that was treated with 9 cycles Therapy-related MDS/AML is a long-term complica- of AZA for minimal residual disease (MRD) (AML1/EVI1 tion of pediatric cancer. Although patients have benefitted fusion transcript) after allogeneic HSCT. The patient from AML-type induction chemotherapy, followed by received 3 cycles of low-dose AZA (32 mg/m2/d) on days 1 HSCT as postremission therapy, childhood t-MDS/AML to 5, and 6 cycles of higher-dose AZA (75 mg/m2/d) on days has a poor prognosis.6 1 to 5, with repeated cycles beginning on day 29. Disruption of chromosome 3q26 is a rare but recurrent The hematological toxicity and infectious complica- cytogenetic aberration that occurs in AML or MDS, and tions associated with AZA treatment were reversible and among several types of 3q26 aberrations, the most common acceptable, and no other toxicities were recognized. The use are inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and t(3;21)(q26.2;q22). of AZA was not associated with exacerbation of GVHD. Shaoying and colleagues have reported clinicopathologic, After 9 cycles of AZA, AML1/EVI1 fusion transcript dis- cytogenetic, and survival data for 17 MDS/AML patients appeared and AZA was discontinued. The patient has been associated with t(3;21)(q26.2;q22) (12 patients had t-MDS, free from recurrence for over 26 months after the HSCT r 2014 Lippincott Williams & Wilkins www.jpho-online.com | e323 Inoue et al J Pediatr Hematol Oncol Volume 36, Number 5, July 2014 and over 14 months after the discontinuance of AZA, 2. Spina F, Alessandrino PE, Milani R, et al. Allogeneic stem cell although he did not achieve a CR before HSCT. transplantation in therapy-related acute myeloid leukemia and The German RELAZA trial evaluated the efficacy of myelodysplastic syndromes: impact of patient characteristics AZA in the setting of MRD-triggered preemptive therapy to and timing of transplant. Leuk Lymphoma. 2012;53:96–102. 3. Bally C, The´pot S, Quesnel B, et al. Azacitidine in the prevent or delay hematological relapse in patients with MDS treatment of therapy related myelodysplastic syndrome and or AML after allogeneic HSCT. After only 4 cycles of AZA acute myeloid leukemia (tMDS/AML): a report on 54 patients 2 (75 mg/m /d for 7 d), the MRD was diminished or stabilized by the Groupe Francophone Des Myelodysplasies (GFM). in 80% of patients (16 of 20 patients) in the absence of a Leuk Res. 2013;37:637–640. hematological relapse. Nevertheless, for 65% of patients, a 4. Lima M, Giralt S, Thall PF, et al. Maintenance therapy with hematological relapse after the initial response could not be low-dose azacitidine after allogeneic hematopoietic stem cell finally prevented; 13 patients eventually relapsed, but the time transplantation for recurrent acute myelogenous leukemia or to relapse was considerably prolonged.5 myelodysplastic syndrome: a dose and schedule finding study. There is no previous data proven that the AML1/EVI1 Cancer. 2010;116:5420–5431. 5. Platzbecker U, Wermke M, Radke J, et al. Azacitidine for gene translocation was eliminated by the AZA therapy. treatment of imminent relapse in MDS or AML patients after However EVI1 expression may be regulated by epigenetic allogeneic HSCT: results of the RELAZA trial. Leukemia. 6 mechanisms involving DNA methylation, so the use of 2012;26:381–389. AZA may have been useful for the EVI1-induced leuke- 6. Aguilera DG, Vaklavas C, Tsimberidou AM, et al. Pediatric mogenesis in this patient. therapy-related myelodysplastic syndrome/acute myeloid leu- Furthermore, recent results suggest that AZA treatment kemia: the MD Anderson Cancer Center experience. J Pediatr of allotransplanted mice mitigates deleterious GVHD while Hematol Oncol. 2009;31:803–811. preserving the beneficial graft-versus-leukemia effect, because 7. Shaoying Li, Cameron Yin C, Medeiros Jeffrey L, et al. AZA induces FOXP3 expression in naive T cells, which in turn Myelodysplasic syndrome/acute myeloid leukemia with 9,10 t(3;21)(q26.2;q22) is commonly a therapy-related disease induces the production of a regulatory T-cell population. associated with poor outcome. Am J Clin Pathol. 2012;138: Preemptive AZA treatment for MRD has an accept- 146–152. able safety profile and appears to be an effective strategy in 8. Vazquez I, Maicas M, Cervera J, et al. Down-regulation of pediatric patients with high-risk MDS after HSCT. There EVI1 is associated with epigenetic alterations and good are little data available about AZA therapy after HSCT in prognosis in patients with acute myeloid leukemia. Hema- pediatric MDS/AML, and therefore, further studies are tologica. 2011;96:1448–1456. needed. 9. Moon C, Kim SH, Park KS, et al. Use of epigenetic modification to induce FOXP3 expression in naı¨ve T cells. Transplant Proc. 2009;41:1848–1854. REFERENCES 10. Choi J, Ritchey J, Prior JL, et al. In vivo administration of 1. Leone G, Pagano L, Ben-Yehuda D, et al. Therapy-related hypomethylating agents mitigate graft-versus-host disease leukemia and myelodysplasia: susceptibility and incidence. without sacrificing graft-versus-leukemia. Blood. 2010;116: Haematologica. 2007;92:1389–1398. 129–139.
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