- Email: [email protected]
natural killer cell precursor acute leukemia treated successfully with acute myeloid leukemia-oriented chemotherapy incorporating l -asparaginase
Leukemia Research 34 (2010) 1677–1679
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Case report
A child with myeloid/natural killer cell precursor acute leukemia treated successfully with acute myeloid leukemia-oriented chemotherapy incorporating l-asparaginase Mizuho Morimoto a , Kensuke Kondoh a,∗ , Dai Keino a , Ryo Ohyama a , Satomi Ban a , Akitoshi Kinoshita a , Toshiyuki Kitoh b,c a
Department of Pediatrics, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae-ku, Kanagawa, Japan Department of Pediatrics, Shiga Medical Center for Children, Shiga, Japan c Department of Pediatrics, Aichi Medical University, Nagakute, Japan b
a r t i c l e
i n f o
Article history: Received 25 May 2010 Received in revised form 19 June 2010 Accepted 19 June 2010 Available online 16 July 2010 Keywords: Asparagine synthetase protein Three-dimensional flow cytometry analysis Minimal residual disease
1. Introduction Myeloid/natural killer (myeloid/NK) cell precursor acute leukemia was initially identified as a leukemia of natural killer (NK) cells, with co-expression of both myeloid and NK cell precursor antigens [1]. The leukemic cells of myeloid/NK cell precursor acute leukemia are negative for myeloperoxidase staining (<3% of total cells) but positive for CD7, CD56, and myeloid antigens [1]. In comparison with other types of NK malignancy, this disease entity is considered to be caused by immature leukemic cells, in terms of morphology, phenotype, and genotype [1]. The prognosis of myeloid/NK cell precursor acute leukemia is reportedly poor. Although chemotherapeutic regimens designed for acute myeloid leukemia (AML) can effective induce complete remission in patients with myeloid/NK cell precursor acute leukemia, most of them subsequently relapse, and there have been no reports of patients surviving for more than 4 years [1]. To our knowledge, all previous reports of long-term remission have involved patients who underwent hematopoietic stem cell transplantation (HSCT) at the time of initial complete remission [2,3]. Recently, l-asparaginase (l-asp) has been shown to induce selective apoptosis of NK cell lymphoma cells in vitro [4]. Indeed, successful
∗ Corresponding author. Tel.: +81 44 977 8111x3321; fax: +81 44 976 8603. E-mail address: [email protected] (K. Kondoh). 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.06.020
therapeutic results have been reported for patients with various kinds of NK cell tumors, including myeloid/NK cell precursor acute leukemia, receiving l-asp-based chemotherapy and HSCT [2,5]. Here we report a 5-year-old girl with myeloid/NK cell precursor acute leukemia, who has maintained long-term remission after receiving AML-oriented chemotherapy incorporating l-asp. 2. Case report A 5-year-old Japanese girl was referred to our hospital because of high fever with pancytopenia. On admission, there was no evidence of lymphadenopathy, hepatosplenomegaly, bleeding tendency, or other abnormality. The hemoglobin concentration was 8.1 g/dl, white blood cell count 1200/l with 8% neutrophils, 85% lymphocytes, and 3.5% leukemic cells, and platelet count 74,000/l. The C-reactive protein level was 10.3 mg/dl, and serum ferritin was 1560 ng/ml. A serological study was negative for Epstein-Barr virus infection. A bone marrow aspirate was hypocellular, with 48.0% leukemic cells. Morphologically, the cells were generally L2-shaped according to the French–American–British classification, and varied in size, showing round to moderately irregular nuclei and prominent nucleoli, with a lack of azurophilic granules in the pale, myeloperoxidase-negative cytoplasm. The immunophenotype of the leukemic cells examined by flow cytometry was: CD45 78.0%, CD2 40.1%, CD3 15.8%, cytoplasmic (cy) CD3 78.9%, CD4 5.7%, CD5 43.3%, CD7 93.2%, CD8 18.7%, CD10 0.7%, CD19 5.5%, CD20 7.9%,
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M. Morimoto et al. / Leukemia Research 34 (2010) 1677–1679
Fig. 1. Clinical course and sequential therapeutic response of the patient. Abbreviations: BM, bone marrow; MRD, minimal residual disease.
CD22 7.3%, CD24 5.9%, CD13 0.6%, CD33 80.2%, CD34 73.1%, CD117 (c-kit) 43.6%, CD14 0.7%, HLA-DR 14.3%, CD56 88.7%, CD244 73.3%, CD41 1.4%, MPO (myeloperoxidase) 3.9%, cyCD79a 8.8%, and TdT 1.2%. The leukemic cells were strongly positive for the myeloid antigen CD33, T-cell antigens cyCD3 and CD7, and NK cell antigen CD56. Chromosomal analysis of bone marrow cells revealed a normal female karyotype. Cerebrospinal fluid examination revealed no central nervous system involvement. Southern blot analysis showed no rearrangement band for TCR or immunoglobulin heavy chain. On the basis of these findings, myeloid/NK cell precursor acute leukemia was diagnosed. Induction chemotherapy was begun with l-asp (10,000 U/m2 ) alone for 5 days, followed by a modified chemotherapeutic regimen for AML consisting of cytosine arabinoside (Ara-C), mitoxantrone (MIT) (Ara-C 200 mg/m2 on day 6–12; MIT 5 mg/m2 on day 6–10) and intrathecal methotrexate, Ara-C and hydrocortisone on day 6. On day 6, at the end of l-asp treatment, a bone marrow aspiration examination was performed, and this showed that the leukemic cells were decreased at 9.6%. Upon hematological recovery after remission induction therapy, we verified that the patient was in complete remission. She then received four courses of consolidation chemotherapy for the modified AML regimen, followed by l-asp (10,000 U/m2 ) for 5 days. Each chemotherapy regimen of the first, second or fourth consolidation therapy consists of Ara-C, etoposide, l-asp (Ara-C 2–3 g/m2 twice daily on day 1–3; etoposide 100 mg/m2 on day 1–5; l-asp 10,000 U/m2 on day 6–10) and treatment with intrathecal methotrexate, Ara-C and hydrocortisone on day 1. The third consolidation therapy consists of Ara-C, idarubicin, l-asp (Ara-C 1.4 g/m2 twice daily on day 1–3; idarubicin 7 mg/m2 on day 1; l-asp 10,000 U/m2 on day 4–8) and treatment with intrathecal methotrexate, Ara-C and hydrocortisone on day 1. At the time of hematological recovery after the last consolidation therapy, we verified that the patient was in complete remission, and we followed her up afterwards at the outpatient clinic. She has since remained in complete remission for over 40 months after the first remission. When the patient was admitted, we examined the expression of asparagine synthetase (AS) protein in her bone marrow cells using a previously reported immunocytochemical method [4], and the results were completely negative. Furthermore, we examined the response to chemotherapy by three-dimensional flow cytometry analysis of her bone marrow cells using antibodies against CD7, CD33, and CD56 for assessment of minimal residual disease (MRD). At diagnosis, we had found that 15.6% of cells were positive for CD7, CD33, and CD56, but after the patient had achieved complete remission, no positivity for these antigens was detectable (Fig. 1).
3. Discussion Suzuki et al. defined the criteria for myeloid/NK cell precursor acute leukemia as acute leukemia or lymphoblastic lymphoma with positivity for CD7, CD56 and myeloid antigen (CD13 or CD33), with a surface CD3-negative phenotype and no myeloperoxidase immunoreactivity [6]. On the basis of these criteria, we diagnosed the present case as myeloid/NK cell precursor acute leukemia. The optimal treatment for myeloid/NK cell precursor acute leukemia remains undetermined. In the present case, chemotherapy for AML seemed to be effective, as has been reported previously [1]. It was noteworthy that the number of leukemic cells decreased after introduction of l-asp alone, and we verified that her leukemic cells were negative for AS. As in vitro studies of leukemic cells have shown an inverse association with sensitivity to l-asp [7], and the clinical effectiveness of l-asp in patients with low expression of AS has been well documented [2,8], l-asp might be a key candidate drug for patients with myeloid/NK cell precursor acute leukemia. The therapeutic response of myeloid/NK cell precursor acute leukemia to AML chemotherapy regimens seems to be better than that to ALL regimens [1]. However, relapse frequently occurs, and the prognosis is poor. Despite intensive treatment, including allogeneic bone marrow transplantation, most patients ultimately die within 41 months [1]. There have been two reports of pediatric cases in which long-term complete remission was achieved after unrelated HSCT, such as cord blood transplantation [3,9]. However, we did not use HSCT for our present patient because she showed a good response to our chemotherapy regimen, as verified by sequential monitoring of MRD using three-dimensional flow cytometry analysis of her bone marrow cells. The patient has since remained in complete remission for a long period. Although the significance of sequential monitoring of MRD as a prognostic marker, as is the case in acute lymphoblastic leukemia [10], has not been clarified in myeloid/NK cell precursor acute leukemia, this issue will require further evaluation. The present case suggests that an effective chemotherapy regimen, even without allogeneic HSCT, may be able to induce longterm remission in patients with myeloid/NK cell precursor acute leukemia.
Conflict of interest None.
M. Morimoto et al. / Leukemia Research 34 (2010) 1677–1679
Acknowledgement This work was not supported by any grant. The authors state that no funding was received. References [1] Suzuki R, Yamamoto K, Seto M, Kagami Y, Ogura M, Yatabe, et al. CD7+ and CD56+ myeloid/natural killer cell precursor acute leukemia: a distinct hematolymphoid disease entity. Blood 1997;90:2417–28. [2] Tezuka K, Nakayama H, Honda K, Suzumiya J, Oshima K, Kitoh T, et al. Treatment of a child with myeloid/NK cell precursor acute leukemia with l-asparaginase and unrelated cord blood transplantation. Int J Hematol 2002;75:201–6. [3] Shimokawa T, Saitoh M, Kojima Y, Takeyama H. Successful treatment of myeloid/natural killer cell precursor acute leukemia with allogeneic peripheral blood stem cell transplantation. Rinsho Ketsueki 2002;43(2):112–6 (in Japanese). [4] Ando M, Sugimoto K, Kitoh T, Sasaki M, Mukai K, Ando J, et al. Selective apoptosis of natural killer-cell tumours by l-asparaginase. Br J Haematol 2005;130:860–8.
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[5] Hyakuna N, Toguchi S, Higa T, Okudaira T, Taira N, Masuda M, et al. Childhood blastic NK cell leukemia successfully treated with l-asparaginase and allogenic bone marrow transplantation. Pediatr Blood Cancer 2004;42:631–4. [6] Suzuki R, Nakamura S. Malignancies of natural killer (NK) cell precursor: myeloid/NK cell precursor acute leukemia and blastic NK cell lymphoma/leukemia. Leukemia Res 1999;23:615–24. [7] Huston RG, Kitoh T, Moraga Amador DA, Cosic S, Schuster SM, Kilberg MS. Amino acid control of asparaginase synthetase: relation to asparaginase resistance in human leukemia cells. Am J Physiol 1997;272(5 pt 1): C1691–9. [8] Nagafuji K, Fujisaki T, Arima F, Ohshima K. l-Asparaginase induced durable remission of relapsed nasal NK/T-cell lymphoma after autologous peripheral blood stem cell transplantation. Int J Hematol 2001;74:447–50. [9] Suminoe A, Matsuzaki A, Takeda H, Hattori H, Furuno K, Takemoto M, et al. An infant with precursor natural killer (NK) cell leukemia successfully treated with an unrelated cord blood transplantation. Leuk Lymphoma 2000;39: 641–6. [10] Katsibardi K, Moschovi MA, Braoudaki M, Papadhimitriou SI, Papathanasiou C, Tzortzatou-Stathopoulou F. Sequential monitoring of minimal residual disease in acute lymphoblastic leukemia: 7-year experience in pediatric hematology/oncology unit. Leuk Lymphoma 2010;51:846–52.
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Case report
A child with myeloid/natural killer cell precursor acute leukemia treated successfully with acute myeloid leukemia-oriented chemotherapy incorporating l-asparaginase Mizuho Morimoto a , Kensuke Kondoh a,∗ , Dai Keino a , Ryo Ohyama a , Satomi Ban a , Akitoshi Kinoshita a , Toshiyuki Kitoh b,c a
Department of Pediatrics, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae-ku, Kanagawa, Japan Department of Pediatrics, Shiga Medical Center for Children, Shiga, Japan c Department of Pediatrics, Aichi Medical University, Nagakute, Japan b
a r t i c l e
i n f o
Article history: Received 25 May 2010 Received in revised form 19 June 2010 Accepted 19 June 2010 Available online 16 July 2010 Keywords: Asparagine synthetase protein Three-dimensional flow cytometry analysis Minimal residual disease
1. Introduction Myeloid/natural killer (myeloid/NK) cell precursor acute leukemia was initially identified as a leukemia of natural killer (NK) cells, with co-expression of both myeloid and NK cell precursor antigens [1]. The leukemic cells of myeloid/NK cell precursor acute leukemia are negative for myeloperoxidase staining (<3% of total cells) but positive for CD7, CD56, and myeloid antigens [1]. In comparison with other types of NK malignancy, this disease entity is considered to be caused by immature leukemic cells, in terms of morphology, phenotype, and genotype [1]. The prognosis of myeloid/NK cell precursor acute leukemia is reportedly poor. Although chemotherapeutic regimens designed for acute myeloid leukemia (AML) can effective induce complete remission in patients with myeloid/NK cell precursor acute leukemia, most of them subsequently relapse, and there have been no reports of patients surviving for more than 4 years [1]. To our knowledge, all previous reports of long-term remission have involved patients who underwent hematopoietic stem cell transplantation (HSCT) at the time of initial complete remission [2,3]. Recently, l-asparaginase (l-asp) has been shown to induce selective apoptosis of NK cell lymphoma cells in vitro [4]. Indeed, successful
∗ Corresponding author. Tel.: +81 44 977 8111x3321; fax: +81 44 976 8603. E-mail address: [email protected] (K. Kondoh). 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.06.020
therapeutic results have been reported for patients with various kinds of NK cell tumors, including myeloid/NK cell precursor acute leukemia, receiving l-asp-based chemotherapy and HSCT [2,5]. Here we report a 5-year-old girl with myeloid/NK cell precursor acute leukemia, who has maintained long-term remission after receiving AML-oriented chemotherapy incorporating l-asp. 2. Case report A 5-year-old Japanese girl was referred to our hospital because of high fever with pancytopenia. On admission, there was no evidence of lymphadenopathy, hepatosplenomegaly, bleeding tendency, or other abnormality. The hemoglobin concentration was 8.1 g/dl, white blood cell count 1200/l with 8% neutrophils, 85% lymphocytes, and 3.5% leukemic cells, and platelet count 74,000/l. The C-reactive protein level was 10.3 mg/dl, and serum ferritin was 1560 ng/ml. A serological study was negative for Epstein-Barr virus infection. A bone marrow aspirate was hypocellular, with 48.0% leukemic cells. Morphologically, the cells were generally L2-shaped according to the French–American–British classification, and varied in size, showing round to moderately irregular nuclei and prominent nucleoli, with a lack of azurophilic granules in the pale, myeloperoxidase-negative cytoplasm. The immunophenotype of the leukemic cells examined by flow cytometry was: CD45 78.0%, CD2 40.1%, CD3 15.8%, cytoplasmic (cy) CD3 78.9%, CD4 5.7%, CD5 43.3%, CD7 93.2%, CD8 18.7%, CD10 0.7%, CD19 5.5%, CD20 7.9%,
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Fig. 1. Clinical course and sequential therapeutic response of the patient. Abbreviations: BM, bone marrow; MRD, minimal residual disease.
CD22 7.3%, CD24 5.9%, CD13 0.6%, CD33 80.2%, CD34 73.1%, CD117 (c-kit) 43.6%, CD14 0.7%, HLA-DR 14.3%, CD56 88.7%, CD244 73.3%, CD41 1.4%, MPO (myeloperoxidase) 3.9%, cyCD79a 8.8%, and TdT 1.2%. The leukemic cells were strongly positive for the myeloid antigen CD33, T-cell antigens cyCD3 and CD7, and NK cell antigen CD56. Chromosomal analysis of bone marrow cells revealed a normal female karyotype. Cerebrospinal fluid examination revealed no central nervous system involvement. Southern blot analysis showed no rearrangement band for TCR or immunoglobulin heavy chain. On the basis of these findings, myeloid/NK cell precursor acute leukemia was diagnosed. Induction chemotherapy was begun with l-asp (10,000 U/m2 ) alone for 5 days, followed by a modified chemotherapeutic regimen for AML consisting of cytosine arabinoside (Ara-C), mitoxantrone (MIT) (Ara-C 200 mg/m2 on day 6–12; MIT 5 mg/m2 on day 6–10) and intrathecal methotrexate, Ara-C and hydrocortisone on day 6. On day 6, at the end of l-asp treatment, a bone marrow aspiration examination was performed, and this showed that the leukemic cells were decreased at 9.6%. Upon hematological recovery after remission induction therapy, we verified that the patient was in complete remission. She then received four courses of consolidation chemotherapy for the modified AML regimen, followed by l-asp (10,000 U/m2 ) for 5 days. Each chemotherapy regimen of the first, second or fourth consolidation therapy consists of Ara-C, etoposide, l-asp (Ara-C 2–3 g/m2 twice daily on day 1–3; etoposide 100 mg/m2 on day 1–5; l-asp 10,000 U/m2 on day 6–10) and treatment with intrathecal methotrexate, Ara-C and hydrocortisone on day 1. The third consolidation therapy consists of Ara-C, idarubicin, l-asp (Ara-C 1.4 g/m2 twice daily on day 1–3; idarubicin 7 mg/m2 on day 1; l-asp 10,000 U/m2 on day 4–8) and treatment with intrathecal methotrexate, Ara-C and hydrocortisone on day 1. At the time of hematological recovery after the last consolidation therapy, we verified that the patient was in complete remission, and we followed her up afterwards at the outpatient clinic. She has since remained in complete remission for over 40 months after the first remission. When the patient was admitted, we examined the expression of asparagine synthetase (AS) protein in her bone marrow cells using a previously reported immunocytochemical method [4], and the results were completely negative. Furthermore, we examined the response to chemotherapy by three-dimensional flow cytometry analysis of her bone marrow cells using antibodies against CD7, CD33, and CD56 for assessment of minimal residual disease (MRD). At diagnosis, we had found that 15.6% of cells were positive for CD7, CD33, and CD56, but after the patient had achieved complete remission, no positivity for these antigens was detectable (Fig. 1).
3. Discussion Suzuki et al. defined the criteria for myeloid/NK cell precursor acute leukemia as acute leukemia or lymphoblastic lymphoma with positivity for CD7, CD56 and myeloid antigen (CD13 or CD33), with a surface CD3-negative phenotype and no myeloperoxidase immunoreactivity [6]. On the basis of these criteria, we diagnosed the present case as myeloid/NK cell precursor acute leukemia. The optimal treatment for myeloid/NK cell precursor acute leukemia remains undetermined. In the present case, chemotherapy for AML seemed to be effective, as has been reported previously [1]. It was noteworthy that the number of leukemic cells decreased after introduction of l-asp alone, and we verified that her leukemic cells were negative for AS. As in vitro studies of leukemic cells have shown an inverse association with sensitivity to l-asp [7], and the clinical effectiveness of l-asp in patients with low expression of AS has been well documented [2,8], l-asp might be a key candidate drug for patients with myeloid/NK cell precursor acute leukemia. The therapeutic response of myeloid/NK cell precursor acute leukemia to AML chemotherapy regimens seems to be better than that to ALL regimens [1]. However, relapse frequently occurs, and the prognosis is poor. Despite intensive treatment, including allogeneic bone marrow transplantation, most patients ultimately die within 41 months [1]. There have been two reports of pediatric cases in which long-term complete remission was achieved after unrelated HSCT, such as cord blood transplantation [3,9]. However, we did not use HSCT for our present patient because she showed a good response to our chemotherapy regimen, as verified by sequential monitoring of MRD using three-dimensional flow cytometry analysis of her bone marrow cells. The patient has since remained in complete remission for a long period. Although the significance of sequential monitoring of MRD as a prognostic marker, as is the case in acute lymphoblastic leukemia [10], has not been clarified in myeloid/NK cell precursor acute leukemia, this issue will require further evaluation. The present case suggests that an effective chemotherapy regimen, even without allogeneic HSCT, may be able to induce longterm remission in patients with myeloid/NK cell precursor acute leukemia.
Conflict of interest None.
M. Morimoto et al. / Leukemia Research 34 (2010) 1677–1679
Acknowledgement This work was not supported by any grant. The authors state that no funding was received. References [1] Suzuki R, Yamamoto K, Seto M, Kagami Y, Ogura M, Yatabe, et al. CD7+ and CD56+ myeloid/natural killer cell precursor acute leukemia: a distinct hematolymphoid disease entity. Blood 1997;90:2417–28. [2] Tezuka K, Nakayama H, Honda K, Suzumiya J, Oshima K, Kitoh T, et al. Treatment of a child with myeloid/NK cell precursor acute leukemia with l-asparaginase and unrelated cord blood transplantation. Int J Hematol 2002;75:201–6. [3] Shimokawa T, Saitoh M, Kojima Y, Takeyama H. Successful treatment of myeloid/natural killer cell precursor acute leukemia with allogeneic peripheral blood stem cell transplantation. Rinsho Ketsueki 2002;43(2):112–6 (in Japanese). [4] Ando M, Sugimoto K, Kitoh T, Sasaki M, Mukai K, Ando J, et al. Selective apoptosis of natural killer-cell tumours by l-asparaginase. Br J Haematol 2005;130:860–8.
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[5] Hyakuna N, Toguchi S, Higa T, Okudaira T, Taira N, Masuda M, et al. Childhood blastic NK cell leukemia successfully treated with l-asparaginase and allogenic bone marrow transplantation. Pediatr Blood Cancer 2004;42:631–4. [6] Suzuki R, Nakamura S. Malignancies of natural killer (NK) cell precursor: myeloid/NK cell precursor acute leukemia and blastic NK cell lymphoma/leukemia. Leukemia Res 1999;23:615–24. [7] Huston RG, Kitoh T, Moraga Amador DA, Cosic S, Schuster SM, Kilberg MS. Amino acid control of asparaginase synthetase: relation to asparaginase resistance in human leukemia cells. Am J Physiol 1997;272(5 pt 1): C1691–9. [8] Nagafuji K, Fujisaki T, Arima F, Ohshima K. l-Asparaginase induced durable remission of relapsed nasal NK/T-cell lymphoma after autologous peripheral blood stem cell transplantation. Int J Hematol 2001;74:447–50. [9] Suminoe A, Matsuzaki A, Takeda H, Hattori H, Furuno K, Takemoto M, et al. An infant with precursor natural killer (NK) cell leukemia successfully treated with an unrelated cord blood transplantation. Leuk Lymphoma 2000;39: 641–6. [10] Katsibardi K, Moschovi MA, Braoudaki M, Papadhimitriou SI, Papathanasiou C, Tzortzatou-Stathopoulou F. Sequential monitoring of minimal residual disease in acute lymphoblastic leukemia: 7-year experience in pediatric hematology/oncology unit. Leuk Lymphoma 2010;51:846–52.