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Myeloproliferative Disease: A Case Report
Case Report Salvage of Donor Graft with Decitabine and Maintenance Post Allogeneic Stem Cell Transplantation in Myelodysplastic/ Myeloproliferative Disease: A Case Report Anastasios Raptis, Mounzer Agha, Megha Shah Abstract Allogeneic stem cell transplantation (ASCT) is the only curative treatment option for patients with myelodysplastic syndrome (MDS). High 1-year ASCT mortality and relapse rates have necessitated the development of novel therapies to improve clinical outcomes. Recently, 5-azacitidine, a DNA hypomethylating agent, was reported to be used for graft salvage in patients undergoing cytogenetic relapse after ASCT. We report a similar case of graft salvage and maintenance after transplantation in an MDS patient using decitabine, another DNA hypomethylating agent known to induce cytogenetic remissions with a manageable side effect profile. Clinical Leukemia, Vol. 3, No. 2, E22-E23, 2009; DOI: 10.3816/CLK.2009.n.010 Keywords: Cytogenetics, Deletion (5q), Immunomodulatory drug, Oral therapy, Transfusion independence
Case Report Treatment of myelodysplastic syndromes (MDS) has traditionally used supportive care: red cell and platelet transfusions; growth factors; immunosuppressant and immunomodulatory therapies such as antithymocyte globulin, cyclosporine, and lenalidomide; and, more recently, hypomethylating agents, such as decitabine.1-3 Currently, allogeneic stem cell transplantation (ASCT) is the only curative option for patients with MDS,4 although the 1-year ASCT mortality rate of 20% to 30%, in addition to the high disease relapse rate of 30% to 40%, indicates that novel therapies are needed to reduce the relapse rate and improve the outcomes of patients undergoing ASCT. Decitabine, a DNA hypomethylating agent with a manageable side effect profile, was introduced as an additional option in MDS treatment with its ability to improve complete remission rates and hematologic profiles as seen in phase III trials comparing decitabine and supportive care.5 In addition, it has been reported to induce cytogenetic remissions (38%) in high-risk patients with MDS with poor cytogenetic profiles. This characteristic supports the investigation of using decitabine posttransplantation to decrease relapse rates. 5-Azacitidine, another DNA hypomethylating agent, has been similarly used for cytogenic relapse posttransplantation in patients receiving ablative conditioning regimens.6 In this report, we present a case study of a patient receiving decitabine after ASCT for donor graft salvage and maintenance. Initially, a 61-year-old man presented with weight loss, shortness of breath, night sweats, fatigue, leukocytosis, and anemia in October 2006 requiring 10 units of packed red blood cells (PRBCs) that month and then another 12 units in December. A bone marrow biopsy revealed the presence of marked hypercellularity with trilineage dysplasia, complex University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA Submitted: Jul 27, 2008; Revised: Sep 18, 2008; Accepted: Oct 15, 2008 Address for correspondence: Anastasios Raptis, MD, University of Pittsburgh Cancer Institute, Hillman Cancer Center, UPCI Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213-1863 Fax: 412-648-6650; e-mail: [email protected] This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
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Clinical Leukemia • August 2009
Figure 1
Percent Chimerism in Bone Marrow or Peripheral Blood in a Patient with Myelodysplastic Syndrome
120 100 80 60 40
3/18/2008
2/18/2008
1/18/2008
12/18/2007
11/18/2007
9/18/2007
10/18/2007
8/18/2007
7/18/2007
6/18/2007
5/18/2007
4/18/2007
3/18/2007
0
2/18/2007
20 1/18/2007
Percent Donor Chimerism
cytogenetic abnormalities, 4% blasts, and Bcr-Abl–negative transcript. The patient was diagnosed with myelodysplastic/myeloproliferative disease and received induction therapy and a subsequent human leukocyte antigen–matched peripheral blood stem cell transplant from a sibling donor in December 2006. He initially experienced 100% donor engraftment, although by March 2007, a bone marrow biopsy displayed a marked decrease in donor chimerism to 7% with 3% residual blasts and hypercellularity (Figure 1) and return to an abnormal cytogenetic profile. In addition, the patient developed anemia and thrombocytopenia, requiring 2 units of PRBCs in March and 10 units in April. Decitabine 20 mg/m2/day × 5 days given every 5 weeks was started in April 2007, and a significant improvement in donor chimerism to 79% was observed after only 1 cycle. Donor chimerism reached 100% by May 2007 after 2 cycles, and the patient again was found to have normal male karyotype. In addition, absolute neutrophil, platelet, and hemoglobin values returned to normal ranges. A bone marrow biopsy from June 2007 showed that the patient was in remission with 1.3% blasts and < 30% cellularity. The dose of decitabine was reduced to 15 mg/m2/day for 5 days given every 5 to 7 weeks in October 2007 and then to 15 mg/m2/day for 3 days in December 2007. Since then, the patient has remained stable and has maintained 100% donor chimerism. Peripheral blood counts have also been maintained in the normal range except for a transient decrease immediately after decitabine administration because of myelosuppression. The patient developed grade 1 graftversus-host disease of the skin within 1 month after initiation of decitabine therapy, which has been managed with an immunosuppressive regimen consisting of tacrolimus and corticosteroids. As of May 2008, the patient continues to receive decitabine every 5 to 7 weeks and is doing well, having established full donor hematopoiesis. Although data from this case study suggest decitabine can be used for salvage therapy to improve chimerism and recovery in patients with MDS after ASCT, further investigation in additional patients is warranted.
Date
Case Report The authors report no relevant potential conflicts of interest.
References 1. Yazji S, Giles FJ, Tsimberidou AM, et al. Antithymocyte globulin (ATG) - based therapy in patients with myelodysplastic syndromes. Leukemia 2003; 17:2101-6. 2. Bouscary D, Legros L, Tulliez M, et al. A non-randomized dose-escalating phase II study of thalidomide for the treatment of patients with low-risk myelodysplastic syndromes: the Thal-SMD-2000 trial of the Groupe Francais des Myelodysplasies. Br J Haematol 2005; 131:609-18. 3. Jabbour E, Issa JP, Garcia-Manero G, et al. Evolution of decitabine development. Cancer 2008; 112:2341-51. 4. Atallah E, Uberti J, Ayash L, et al. Fifteen-year followup of allogeneic stem cell transplantation in patients with myelodysplastic syndromes using busulfan-based regimens. Blood 2005; 106:5461. 5. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a Phase III randomized study. Cancer 2006; 106:1794-803. 6. Rossetti JM, Shadduck RK, Thatikonda C, et al. Low-dose azacitidine for relapse of MDS/AML after unrelated donor peripheral blood stem cell transplantation. Blood 2007; 110 (Abstract 5034).
Clinical Leukemia • August 2009
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Case Report Treatment of myelodysplastic syndromes (MDS) has traditionally used supportive care: red cell and platelet transfusions; growth factors; immunosuppressant and immunomodulatory therapies such as antithymocyte globulin, cyclosporine, and lenalidomide; and, more recently, hypomethylating agents, such as decitabine.1-3 Currently, allogeneic stem cell transplantation (ASCT) is the only curative option for patients with MDS,4 although the 1-year ASCT mortality rate of 20% to 30%, in addition to the high disease relapse rate of 30% to 40%, indicates that novel therapies are needed to reduce the relapse rate and improve the outcomes of patients undergoing ASCT. Decitabine, a DNA hypomethylating agent with a manageable side effect profile, was introduced as an additional option in MDS treatment with its ability to improve complete remission rates and hematologic profiles as seen in phase III trials comparing decitabine and supportive care.5 In addition, it has been reported to induce cytogenetic remissions (38%) in high-risk patients with MDS with poor cytogenetic profiles. This characteristic supports the investigation of using decitabine posttransplantation to decrease relapse rates. 5-Azacitidine, another DNA hypomethylating agent, has been similarly used for cytogenic relapse posttransplantation in patients receiving ablative conditioning regimens.6 In this report, we present a case study of a patient receiving decitabine after ASCT for donor graft salvage and maintenance. Initially, a 61-year-old man presented with weight loss, shortness of breath, night sweats, fatigue, leukocytosis, and anemia in October 2006 requiring 10 units of packed red blood cells (PRBCs) that month and then another 12 units in December. A bone marrow biopsy revealed the presence of marked hypercellularity with trilineage dysplasia, complex University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA Submitted: Jul 27, 2008; Revised: Sep 18, 2008; Accepted: Oct 15, 2008 Address for correspondence: Anastasios Raptis, MD, University of Pittsburgh Cancer Institute, Hillman Cancer Center, UPCI Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213-1863 Fax: 412-648-6650; e-mail: [email protected] This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
E22
Clinical Leukemia • August 2009
Figure 1
Percent Chimerism in Bone Marrow or Peripheral Blood in a Patient with Myelodysplastic Syndrome
120 100 80 60 40
3/18/2008
2/18/2008
1/18/2008
12/18/2007
11/18/2007
9/18/2007
10/18/2007
8/18/2007
7/18/2007
6/18/2007
5/18/2007
4/18/2007
3/18/2007
0
2/18/2007
20 1/18/2007
Percent Donor Chimerism
cytogenetic abnormalities, 4% blasts, and Bcr-Abl–negative transcript. The patient was diagnosed with myelodysplastic/myeloproliferative disease and received induction therapy and a subsequent human leukocyte antigen–matched peripheral blood stem cell transplant from a sibling donor in December 2006. He initially experienced 100% donor engraftment, although by March 2007, a bone marrow biopsy displayed a marked decrease in donor chimerism to 7% with 3% residual blasts and hypercellularity (Figure 1) and return to an abnormal cytogenetic profile. In addition, the patient developed anemia and thrombocytopenia, requiring 2 units of PRBCs in March and 10 units in April. Decitabine 20 mg/m2/day × 5 days given every 5 weeks was started in April 2007, and a significant improvement in donor chimerism to 79% was observed after only 1 cycle. Donor chimerism reached 100% by May 2007 after 2 cycles, and the patient again was found to have normal male karyotype. In addition, absolute neutrophil, platelet, and hemoglobin values returned to normal ranges. A bone marrow biopsy from June 2007 showed that the patient was in remission with 1.3% blasts and < 30% cellularity. The dose of decitabine was reduced to 15 mg/m2/day for 5 days given every 5 to 7 weeks in October 2007 and then to 15 mg/m2/day for 3 days in December 2007. Since then, the patient has remained stable and has maintained 100% donor chimerism. Peripheral blood counts have also been maintained in the normal range except for a transient decrease immediately after decitabine administration because of myelosuppression. The patient developed grade 1 graftversus-host disease of the skin within 1 month after initiation of decitabine therapy, which has been managed with an immunosuppressive regimen consisting of tacrolimus and corticosteroids. As of May 2008, the patient continues to receive decitabine every 5 to 7 weeks and is doing well, having established full donor hematopoiesis. Although data from this case study suggest decitabine can be used for salvage therapy to improve chimerism and recovery in patients with MDS after ASCT, further investigation in additional patients is warranted.
Date
Case Report The authors report no relevant potential conflicts of interest.
References 1. Yazji S, Giles FJ, Tsimberidou AM, et al. Antithymocyte globulin (ATG) - based therapy in patients with myelodysplastic syndromes. Leukemia 2003; 17:2101-6. 2. Bouscary D, Legros L, Tulliez M, et al. A non-randomized dose-escalating phase II study of thalidomide for the treatment of patients with low-risk myelodysplastic syndromes: the Thal-SMD-2000 trial of the Groupe Francais des Myelodysplasies. Br J Haematol 2005; 131:609-18. 3. Jabbour E, Issa JP, Garcia-Manero G, et al. Evolution of decitabine development. Cancer 2008; 112:2341-51. 4. Atallah E, Uberti J, Ayash L, et al. Fifteen-year followup of allogeneic stem cell transplantation in patients with myelodysplastic syndromes using busulfan-based regimens. Blood 2005; 106:5461. 5. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a Phase III randomized study. Cancer 2006; 106:1794-803. 6. Rossetti JM, Shadduck RK, Thatikonda C, et al. Low-dose azacitidine for relapse of MDS/AML after unrelated donor peripheral blood stem cell transplantation. Blood 2007; 110 (Abstract 5034).
Clinical Leukemia • August 2009
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