- Email: [email protected]
Late onset aplastic anemia during treatment of chronic myeloid leukemia with imatinib mesylate
414
Letters to the Editor / Leukemia Research 31 (2007) 411–419
increase in NK cells, and both CD4+ and CD8+ T cells, and an upregulation of IL-2 receptors on lymphocytes following IL-2 treatment of patients who were immunodeficient following treatment with 2-chlordeoxyadenosine. On the other hand Kasamon et al. [3] found no protection against the fall in CD4+ T cells when IL-2 was given with fludarabine and cyclophosphamide. Viral warts are caused by an infection with papovavirus. They are normally treated with a variety of local therapies and irrespective of which is used they may usually be expected to resolve spontaneously within 3 months. In patients with lymphoma they are more difficult to clear and in this patient they had been getting worse over 6 years. In this case it seems likely that the treatment with IL-2 was effective and it may be that IL-2 may have a part to play in improving the immunodeficiency of CLL. Acknowledgement Professor Hamblin is supported by Tenovus. References [1] Morrison VA. Infections in patients with chronic lymphocytic leukemia: pathogenesis, spectrum and therapeutic approaches. In: Cheson BD, editor. Chronic lymphoid leukkemias: second edition, revised and expanded. New York: Marcel Dekker; 2001. p. 505–24. [2] Dmoszynska A, Legiec W, Wach M. Attempted reconstruction of the immune system using low doses of interleukin 2 in chronic lymphocytic leukemia patients treated with 2-chlorodeoxyadenosine: results of a pilot study. Leuk Lymphoma 1999;34:335–40. [3] Kasamon YL, Flinn IW, Grever MR, Diehl LF, Garrett-Mayer E, Goodman SN, et al. Phase I study of low-dose interleukin-2, fludarabine, and cyclophosphamide for previously untreated indolent lymphoma and chronic lymphocytic leukemia. Clin Cancer Res 2005;11: 8413–7.
Terry J. Hamblin ∗ Department of Haematology, Royal Bournemouth Hospital, Castle Lane East, Bournemouth BH 7 7DW, United Kingdom ∗ Tel.:
+44 1202 267154; fax: +44 1202 300248 E-mail address: [email protected] 4 August 2006 Available online 22 September 2006
doi: 10.1016/j.leukres.2006.08.003
Late onset aplastic anemia during treatment of chronic myeloid leukemia with imatinib mesylate To the Editor, Imatinib mesylate (imatinib; GleevecTM ) is a selective inhibitor of BCR-ABL tyrosine kinase [1] and currently con-
stitutes first line treatment for chronic myeloid leukemia (CML) [2]. We report a case of severe aplastic anemia (SAA) that occurred nearly 3 years into treatment of CML with imatinib. Empiric treatment with high-dose intravenous immunoglobulin (IVIG) and prednisone was associated with a favorable response.
1. Case report A 47 year old previously healthy woman was diagnosed with CML in 1994. Cytogenetic studies revealed 100% Philadelphia chromosome (Ph) metaphases. She was treated with hydroxyurea until August 2003 at which time there was evidence of disease progression with increased splenomegaly, anemia (hemoglobin (Hgb) level 6.6 g/dL), and increased white blood cell count (WBC) of 20.8 × 109 L−1 with 18% blasts. Complete blood count (CBC) 2 weeks later showed transformation to blast phase CML with WBC of 129 × 109 L−1 with 28% blasts, and she was started on imatinib 300 mg daily. She achieved complete hematologic response within 6 weeks and imatinib was titrated to between 500 and 600 mg daily. Follow-up cytogenetic and molecular studies were not performed. In November 2005 she was noted to have leukocytosis with WBC of 13.3 × 109 L−1 suggesting relapse, however BCR-ABL cytogenetic or molecular studies were not performed. Imatinib was continued as her only outpatient medication. In June 2006 she presented with oral candidiasis, and a CBC revealed severe pancytopenia with a WBC count of 0.2 × 109 L−1 , Hgb 4.6 g/dL, and platelet count of 34 × 109 L−1 . Fluconazole for oral candidiasis and levofloxacin for infection prophylaxis were initiated. She received pegfilgrastim 6 mg at 1-week follow up, with no improvement of her neutropenia. The following day she was admitted for neutropenic fever and intractable bleeding of herpes labialis. Blood cultures were positive for methicillin-resistant Staphylococcus aureus, which was thought to be community-acquired. Chest CT showed bilateral diffuse nodular infiltrates. Fungal serology was positive for histoplasma (1:8), however histoplasma urinary antigen was negative. Bone marrow biopsy approximately 1 month after discontinuation of imatinib showed marrow aplasia with cellularity of less than 5%, one of four identifiable metaphases was Ph positive. Peripheral blood fluorescent in situ hybridization showed that 41.4% of 500 nuclei had fusion of BCR and ABL signals, and BCR/ABL mRNA transcripts detected using real-time polymerase chain reaction showed a 0.69 log reduction from an average patient’s level at diagnosis. Fluorescent proaerolysin variant (FLAER) and CD59 flow cytometry were negative for paroxysmal nocturnal hemoglobinuria, and mitomycin C chromosome fragility test was negative for Fanconi’s anemia. Serologies for human immunodeficiency virus, hepatitis B, hepatitis C, Ebstein–Barr virus, cytomegalovirus, parvovirus, and anti-nuclear antibody were negative. On admission to our hospital, Hgb was 9.1 g/dL, WBC 0.4 × 109 L−1 , and
Letters to the Editor / Leukemia Research 31 (2007) 411–419
platelets were 9 × 109 L−1 .Intravenous immunoglobulin 1 g/kg and 60 mg of prednisone were administered for 2 days. Hgb was then 8.2 g/dL, WBC increased to 0.9 × 109 L−1 , and platelets were 29 × 109 L−1 . Prednisone was then decreased to 40 mg daily and IVIG was discontinued. At dismissal, 8 days after admission Hgb was 10.6 g/dL, WBC improved to 2.4 × 109 L−1 , and platelets were 20 × 109 L−1 .
415
Acknowledgements This work was not supported by any outside funding. All authors have contributed to this “Letter to the Editor” and have read and approved the final version of this manuscript.
References
2. Discussion Side effects of imatinib are minimal to moderate in severity, commonly including nausea/vomiting, myalgias, edema, diarrhea, rash, and myelosuppression [3,4]. Myelosuppression occurs in up to 45% of patients with CML receiving imatinib, but commonly resolves with cessation of the medication [4]. In previously untreated patients, grade 4 neutropenia occurs in 2% and grade 4 thrombocytopenia and anemia in <1% of patients [2]. Several case reports have described SAA in patients receiving imatinib after 17–128 days of therapy [5,6]. Chng and Tan reported a case of late onset marrow aplasia in a patient with CML 128 days after starting imatinib. Grade 4 pancytopenia persisted more than 70 days after stopping imatinib [7]. Lewalle et al. reported a case of a 59-year-old female who developed SAA after 2 months of imatinib therapy. She was successfully treated with autologous peripheral blood stem cells collected at the time of diagnosis with continuation of imatinib. A bone marrow biopsy 4 months after stem cell infusion showed a repopulated marrow, with no Ph-positive cells by cytogenetics or FISH [8]. Several hypotheses have been proposed to explain the mechanism by which SAA may develop in CML patients receiving imatinib. Ph/Bcr-Abl-negative clonal chromosomal abnormalities have been shown to develop in patients receiving imatinib [9]. It is possible these abnormal clones could cause SAA through an autoimmune response by exposure of cryptic epitopes through molecular mimicry [10]. In addition to inhibiting BCR-ABL, imatinib has been shown to have a dose-dependent decrease in CD34+ stem cell proliferation in vitro, which may contribute to patient’s myelosuppression [11] and could be extrapolated to contribute to aplastic anemia. Imatinib has also been used to treat gastrointestinal stromal tumors due to its inhibition of c-kit expression. Bone marrow stem cells also have increased c-kit activity; therefore an inhibitory effect of imatinib on c-kit in bone marrow stem cells may contribute to myelosuppression [12]. Imatinib may be associated with late-onset SAA in CML patients; this effect may be mediated by several possible mechanisms. Our patient’s pancytopenia did not improve after discontinuation of imatinib, but did respond to a combination of IVIG and prednisone. One month later, the leukocyte count normalized, platelet count increased to 45 × 109 /L and hemoglobin level remained above 10 g/dL without transfusions.
[1] Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038–42. [2] O’Brien SG, Guilhot F, Larson R, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994–1004. [3] Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of the BCRABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344(14):1031–7. [4] Sneed TB, Hagop MK, O’Brian S, et al. The significance of myelosupression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Cancer 2004;100(1):116–21. [5] Lokeshwar N, Kumar L, Kumari M. Severe bone marrow aplasia following imatinib mesylate in a patient with chronic myelogenous leukemia. Leuk Lymphoma 2005;46(5):781–4. [6] Sumi M, Tauchi T, Shimamoto Y, Sshudia G, Nakajima A, Ito Y, et al. Chronic myeloid leukemia associated with sustained severe pancytopenia after imatinib therapy. Rinsho Ketsueki 2002;43:868–70. [7] Chng WJ, Tan LH. Late-onset marrow aplasia due to imatinib in newly diagnosed chronic phase chronic myeloid leukemia. Leuk Res 2005;29(6):719–20. [8] Lewalle P, Meuleman N, Verhest A, Bron D, Martiat P. Infusion of peripheral blood stem cells collected at diagnosis, with maintenance of the treatment, resulted in Ph-negative recovery in a chronic myeloid leukaemia patient in persisting aplasia on STI-571 therapy. Br J Haematol 2002;118(1):144–6. [9] Schmitt-Graeff A, Hochhaus A. Hematological side effects of tyrosine kinase inhibition using imatinib. Pathogen 2006;27(1):40–6. [10] Brodsky RA, Jones RJ. Riddle: what do aplastic anemia, acute promyelocytic leukemia, and chronic myeloid leukemia have in common? Leukemia 2004;18(10):1740–2 [review]. [11] Bartolovic K, Balabanov S, Hartmann U, et al. Inhibitory effect of imatinib on normal progenitor cells in vitro. Blood 2004;103(2):523–9. [12] Ogawa M, Matsuzaki Y, Nishikawa S, et al. Expression and function of c-kit in hematopoietic prgenitor cells. J Exp Med 1991;171(1):63–71.
G. LeMarbre C. Schinstock R. Hoyer J. Krook A. Tefferi ∗ Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States ∗ Corresponding
author. Tel.: +1 507 284 3159. E-mail address: [email protected] (A. Tefferi) 14 August 2006 Available online 28 September 2006 doi: 10.1016/j.leukres.2006.08.011
Letters to the Editor / Leukemia Research 31 (2007) 411–419
increase in NK cells, and both CD4+ and CD8+ T cells, and an upregulation of IL-2 receptors on lymphocytes following IL-2 treatment of patients who were immunodeficient following treatment with 2-chlordeoxyadenosine. On the other hand Kasamon et al. [3] found no protection against the fall in CD4+ T cells when IL-2 was given with fludarabine and cyclophosphamide. Viral warts are caused by an infection with papovavirus. They are normally treated with a variety of local therapies and irrespective of which is used they may usually be expected to resolve spontaneously within 3 months. In patients with lymphoma they are more difficult to clear and in this patient they had been getting worse over 6 years. In this case it seems likely that the treatment with IL-2 was effective and it may be that IL-2 may have a part to play in improving the immunodeficiency of CLL. Acknowledgement Professor Hamblin is supported by Tenovus. References [1] Morrison VA. Infections in patients with chronic lymphocytic leukemia: pathogenesis, spectrum and therapeutic approaches. In: Cheson BD, editor. Chronic lymphoid leukkemias: second edition, revised and expanded. New York: Marcel Dekker; 2001. p. 505–24. [2] Dmoszynska A, Legiec W, Wach M. Attempted reconstruction of the immune system using low doses of interleukin 2 in chronic lymphocytic leukemia patients treated with 2-chlorodeoxyadenosine: results of a pilot study. Leuk Lymphoma 1999;34:335–40. [3] Kasamon YL, Flinn IW, Grever MR, Diehl LF, Garrett-Mayer E, Goodman SN, et al. Phase I study of low-dose interleukin-2, fludarabine, and cyclophosphamide for previously untreated indolent lymphoma and chronic lymphocytic leukemia. Clin Cancer Res 2005;11: 8413–7.
Terry J. Hamblin ∗ Department of Haematology, Royal Bournemouth Hospital, Castle Lane East, Bournemouth BH 7 7DW, United Kingdom ∗ Tel.:
+44 1202 267154; fax: +44 1202 300248 E-mail address: [email protected] 4 August 2006 Available online 22 September 2006
doi: 10.1016/j.leukres.2006.08.003
Late onset aplastic anemia during treatment of chronic myeloid leukemia with imatinib mesylate To the Editor, Imatinib mesylate (imatinib; GleevecTM ) is a selective inhibitor of BCR-ABL tyrosine kinase [1] and currently con-
stitutes first line treatment for chronic myeloid leukemia (CML) [2]. We report a case of severe aplastic anemia (SAA) that occurred nearly 3 years into treatment of CML with imatinib. Empiric treatment with high-dose intravenous immunoglobulin (IVIG) and prednisone was associated with a favorable response.
1. Case report A 47 year old previously healthy woman was diagnosed with CML in 1994. Cytogenetic studies revealed 100% Philadelphia chromosome (Ph) metaphases. She was treated with hydroxyurea until August 2003 at which time there was evidence of disease progression with increased splenomegaly, anemia (hemoglobin (Hgb) level 6.6 g/dL), and increased white blood cell count (WBC) of 20.8 × 109 L−1 with 18% blasts. Complete blood count (CBC) 2 weeks later showed transformation to blast phase CML with WBC of 129 × 109 L−1 with 28% blasts, and she was started on imatinib 300 mg daily. She achieved complete hematologic response within 6 weeks and imatinib was titrated to between 500 and 600 mg daily. Follow-up cytogenetic and molecular studies were not performed. In November 2005 she was noted to have leukocytosis with WBC of 13.3 × 109 L−1 suggesting relapse, however BCR-ABL cytogenetic or molecular studies were not performed. Imatinib was continued as her only outpatient medication. In June 2006 she presented with oral candidiasis, and a CBC revealed severe pancytopenia with a WBC count of 0.2 × 109 L−1 , Hgb 4.6 g/dL, and platelet count of 34 × 109 L−1 . Fluconazole for oral candidiasis and levofloxacin for infection prophylaxis were initiated. She received pegfilgrastim 6 mg at 1-week follow up, with no improvement of her neutropenia. The following day she was admitted for neutropenic fever and intractable bleeding of herpes labialis. Blood cultures were positive for methicillin-resistant Staphylococcus aureus, which was thought to be community-acquired. Chest CT showed bilateral diffuse nodular infiltrates. Fungal serology was positive for histoplasma (1:8), however histoplasma urinary antigen was negative. Bone marrow biopsy approximately 1 month after discontinuation of imatinib showed marrow aplasia with cellularity of less than 5%, one of four identifiable metaphases was Ph positive. Peripheral blood fluorescent in situ hybridization showed that 41.4% of 500 nuclei had fusion of BCR and ABL signals, and BCR/ABL mRNA transcripts detected using real-time polymerase chain reaction showed a 0.69 log reduction from an average patient’s level at diagnosis. Fluorescent proaerolysin variant (FLAER) and CD59 flow cytometry were negative for paroxysmal nocturnal hemoglobinuria, and mitomycin C chromosome fragility test was negative for Fanconi’s anemia. Serologies for human immunodeficiency virus, hepatitis B, hepatitis C, Ebstein–Barr virus, cytomegalovirus, parvovirus, and anti-nuclear antibody were negative. On admission to our hospital, Hgb was 9.1 g/dL, WBC 0.4 × 109 L−1 , and
Letters to the Editor / Leukemia Research 31 (2007) 411–419
platelets were 9 × 109 L−1 .Intravenous immunoglobulin 1 g/kg and 60 mg of prednisone were administered for 2 days. Hgb was then 8.2 g/dL, WBC increased to 0.9 × 109 L−1 , and platelets were 29 × 109 L−1 . Prednisone was then decreased to 40 mg daily and IVIG was discontinued. At dismissal, 8 days after admission Hgb was 10.6 g/dL, WBC improved to 2.4 × 109 L−1 , and platelets were 20 × 109 L−1 .
415
Acknowledgements This work was not supported by any outside funding. All authors have contributed to this “Letter to the Editor” and have read and approved the final version of this manuscript.
References
2. Discussion Side effects of imatinib are minimal to moderate in severity, commonly including nausea/vomiting, myalgias, edema, diarrhea, rash, and myelosuppression [3,4]. Myelosuppression occurs in up to 45% of patients with CML receiving imatinib, but commonly resolves with cessation of the medication [4]. In previously untreated patients, grade 4 neutropenia occurs in 2% and grade 4 thrombocytopenia and anemia in <1% of patients [2]. Several case reports have described SAA in patients receiving imatinib after 17–128 days of therapy [5,6]. Chng and Tan reported a case of late onset marrow aplasia in a patient with CML 128 days after starting imatinib. Grade 4 pancytopenia persisted more than 70 days after stopping imatinib [7]. Lewalle et al. reported a case of a 59-year-old female who developed SAA after 2 months of imatinib therapy. She was successfully treated with autologous peripheral blood stem cells collected at the time of diagnosis with continuation of imatinib. A bone marrow biopsy 4 months after stem cell infusion showed a repopulated marrow, with no Ph-positive cells by cytogenetics or FISH [8]. Several hypotheses have been proposed to explain the mechanism by which SAA may develop in CML patients receiving imatinib. Ph/Bcr-Abl-negative clonal chromosomal abnormalities have been shown to develop in patients receiving imatinib [9]. It is possible these abnormal clones could cause SAA through an autoimmune response by exposure of cryptic epitopes through molecular mimicry [10]. In addition to inhibiting BCR-ABL, imatinib has been shown to have a dose-dependent decrease in CD34+ stem cell proliferation in vitro, which may contribute to patient’s myelosuppression [11] and could be extrapolated to contribute to aplastic anemia. Imatinib has also been used to treat gastrointestinal stromal tumors due to its inhibition of c-kit expression. Bone marrow stem cells also have increased c-kit activity; therefore an inhibitory effect of imatinib on c-kit in bone marrow stem cells may contribute to myelosuppression [12]. Imatinib may be associated with late-onset SAA in CML patients; this effect may be mediated by several possible mechanisms. Our patient’s pancytopenia did not improve after discontinuation of imatinib, but did respond to a combination of IVIG and prednisone. One month later, the leukocyte count normalized, platelet count increased to 45 × 109 /L and hemoglobin level remained above 10 g/dL without transfusions.
[1] Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038–42. [2] O’Brien SG, Guilhot F, Larson R, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994–1004. [3] Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of the BCRABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344(14):1031–7. [4] Sneed TB, Hagop MK, O’Brian S, et al. The significance of myelosupression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Cancer 2004;100(1):116–21. [5] Lokeshwar N, Kumar L, Kumari M. Severe bone marrow aplasia following imatinib mesylate in a patient with chronic myelogenous leukemia. Leuk Lymphoma 2005;46(5):781–4. [6] Sumi M, Tauchi T, Shimamoto Y, Sshudia G, Nakajima A, Ito Y, et al. Chronic myeloid leukemia associated with sustained severe pancytopenia after imatinib therapy. Rinsho Ketsueki 2002;43:868–70. [7] Chng WJ, Tan LH. Late-onset marrow aplasia due to imatinib in newly diagnosed chronic phase chronic myeloid leukemia. Leuk Res 2005;29(6):719–20. [8] Lewalle P, Meuleman N, Verhest A, Bron D, Martiat P. Infusion of peripheral blood stem cells collected at diagnosis, with maintenance of the treatment, resulted in Ph-negative recovery in a chronic myeloid leukaemia patient in persisting aplasia on STI-571 therapy. Br J Haematol 2002;118(1):144–6. [9] Schmitt-Graeff A, Hochhaus A. Hematological side effects of tyrosine kinase inhibition using imatinib. Pathogen 2006;27(1):40–6. [10] Brodsky RA, Jones RJ. Riddle: what do aplastic anemia, acute promyelocytic leukemia, and chronic myeloid leukemia have in common? Leukemia 2004;18(10):1740–2 [review]. [11] Bartolovic K, Balabanov S, Hartmann U, et al. Inhibitory effect of imatinib on normal progenitor cells in vitro. Blood 2004;103(2):523–9. [12] Ogawa M, Matsuzaki Y, Nishikawa S, et al. Expression and function of c-kit in hematopoietic prgenitor cells. J Exp Med 1991;171(1):63–71.
G. LeMarbre C. Schinstock R. Hoyer J. Krook A. Tefferi ∗ Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States ∗ Corresponding
author. Tel.: +1 507 284 3159. E-mail address: [email protected] (A. Tefferi) 14 August 2006 Available online 28 September 2006 doi: 10.1016/j.leukres.2006.08.011