Acute myeloid leukemia with severe aplastic anemia following immunosuppressive therapy
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《美国医学杂志》
Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
Abstract
Severe aplastic anemia (AA) is a life-threatening condition wherein bone marrow transplantation (BMT) is the therapy of choice in a young patient who has a matched sibling donor. Here, we report an 11-year-old boy with severe AA who was referred for BMT late in its course when he had developed acute myeloid leukemia following two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin. He was then treated with induction therapy using cytosine arabinoside and daunomycin for acute myeloid leukemia, but he succumbed due to infection and refractory leukemia. We discuss the relevance of early referral for BMT in severe AA.
Keywords: Aplastic anemia; Bone marrow transplantation; Immunosuppressive therapy; Leukemia
Aplastic anemia (AA) is a potentially life-threatening failure of hemopoiesis characterized by pancytopenia and bone marrow aplasia. Classification of AA depends on degree of peripheral blood pancytopenia. Severe AA is defined by bone marrow cellularity < 25% and very low values of at least 2/3 hemopoietic lineages: absolute neutrophil count (ANC) < 500/mm 3, platelet count <20,000/mm 3, and reticulocyte count <60,000/mm. 3 Very severe AA meets the same criteria except that ANC < 200/mm. 3 The 2-year mortality rate with supportive care in severe or very severe AA is 80% with invasive fungal infections, bacterial sepsis and bleeding manifestations being the most common cause of death.[1],[2] The current modalities of treatment for severe AA include immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporin or allogenic matched-sibling bone marrow transplantation (BMT). Although IST may result in a response rate of > 70% in severe AA, patients are not considered cured because of high rates of relapse and development of clonal disease[3],[4]. Here, we report a case of severe AA who was referred for BMT late in its course and discuss the relevance of early referral for BMT in this condition.
Case Report
An 11-year-old boy, a known case of severe AA was referred for BMT after having failed two courses of IST. He was initially treated with treated with antilymphocyte globulin and cyclosporin in December 1999 at an outside hospital; cyclosporin was continued till April 2003. Two months after stopping cyclosporine, his counts started falling and cyclosporin was reintroduced but there was poor response. He was then given a repeat course of ATG and cyclosporine in November 2003 without any response. His HLA matching was done and he showed identical match with his elder sister. Studies for paroxysmal nocturnal hemoglobinuria (PNH) were normal. He was referred in April 2004 for allogenic BMT. Physical examination revealed a febrile patient with marked pallor, gum hypertrophy, left orchitis and hepatosplenomegaly of 2 cm each. Investigations revealed hemoglobin 6g/dL, platelet count 40,000/mm 3, white blood cell count 67,200/mm 3; peripheral smear showed 37% myeloblasts. Bone marrow examination confirmed a diagnosis of acute monocytic leukemia (AML-M5); bone marrow cytogenetics revealed normal male karyotype with no evidence of any abnormality. His chest radiograph revealed right lower lobe pneumonitis with pleural effusion.
He was treated with intravenous antibiotics and amphotericin B. Fever subsided and he was started on 3 + 7 induction therapy (daunomycin 60 mg/m 2sub infusion daily for three days and cytosine arabinoside 100 mg/m 2 for seven days as continuous infusion). There was recurrence of fever during induction with evidence of chest infection. CT chest done revealed right side loculated effusion, consolidation in the left upper lobe and bilateral lower lobes along with small pretracheal and left hilar nodes. On this basis, antitubercular therapy was started in addition to antibiotics and antifungal therapy. Day 22 marrow was not in remission and showed 40% blasts. He was then started on reinduction with daunomycin (50 mg/m2 for 3 days), cytosine arabinoside (100 mg/m 2sub every 12 hourly intravenous push for 10 days) and etoposide (100 mg/m 2sub for 5 days). However, the patient developed progressively worsening pneumonia unresponsive to antimicrobial therapy. The child died of septicemia, pneumonia and disseminated intravascular coagulation.
Discussion
The decision for type of treatment (BMT or IST) depends on age of patient, severity of AA and type of allograft (matched sibling or matched unrelated donor). HLA-matched sibling transplant is treatment of choice in young patients (<40 years) with severe AA.[1],[2] However, only 30 % patients have a matched sibling donor. In patients < 30 years of age, cure rates of 70% to 90% are achieved with HLA-matched sibling BMT donor.[5] Since a matched donor was available, an allogenic BMT should have been the treatment of choice in our case.
European BMT registry data suggested that ANC and patient age are predictors of outcome for BMT and IST. BMT is superior to IST in children regardless of ANC and adults up to 40 yrs with low ANC < 300/mm.[3] IST is superior in adults more than 40 years of age and either BMT or IST may be appropriate in patients aged 10-40 years with ANC >300/mm.[5],[6] However, there is a higher risk of late death in patients treated with IST owing to relapse of AA, MDS, acute leukemia or PNH.[7] BMT using matched unrelated donors or mismatched donors is reserved for patients failing IST.[8]
IST is used in patients who are not candidates for BMT. Response to ATG occurs in 50% by 3 months and 75% by 6 months. Some patients are cyclosporine sensitive and require longer course of cyclosporine and also a very slow tapering. Relapse occurs in 30% when cyclosporin is stopped at 6 months. 15% of children and adults with acquired AA develop MDS or associated AML after IST.[7],[9] Whether this is treatment related or due to longer survival after IST allowing time for these underlying clones to expand is not clear. Even before IST, 5% patients showed progression to clonal hemopoiesis[7]. These patients with MDS/AML show chromosome 5, 7 or 8 abnormalities; monosomy 7 is the most common anomaly. Reports of evolution of AA into acute monocytic leukemia are also known, which may be either therapy-related or following a period of MDS[10],[11].
In a study, 12/113 patients children with AA treated with IST developed MDS/AML at 9-81 months following diagnosis; number of days of G-CSF therapy and nonresponse to IST at 6 months being significant risk factors.[9] Socie' et al analyzed 860 patients of severe AA who received IST and 748 patients who received BMT. 42 malignant conditions were reported in 860 patients who received IST: 19 cases of MDS, 15 cases of acute leukemia, 1 case of non-Hodgkin's lymphoma and 7 solid tumors. On the other hand, only 9 were reported in 748 patients who received BMT: 2 cases of acute leukemia and 7 solid tumors.[12]
A common problem in multi-transfused patients with AA compared with leukemia patients is that they may develop alloimmunization to leucocytes present in red cell and platelet transfusions by generating HLA or non-HLA (minor histocompatibility) antibodies. This can result in platelet refractoriness, as well as an increased risk of graft rejection after allogenic BMT.[13] In a retrospective study, incidence of HLA alloimmunization was reported to be 50% in patients with AA who had received blood products prior to introduction of prestorage leucocyte depletion in UK compared with 12% for patients who received only leucocyte-depleted blood products.[14]
Thus, young patients with severe AA should undergo HLA matching at the time of diagnosis and if HLA match is available they should be given the option of BMT. This is especially important as outcome of BMT is significantly better if it is done early rather than late in course of the disease before being multi-transfused and development of clonal disease.
References
1. Brodsky RA, Jones RJ. Aplastic Anemia . Lancet 2005; 365 : 1647-1656.
2. Marsh JC. Management of acquired aplastic anaemia. Blood Rev 2005; 19 : 143-151.
3. Kojima S, Horibe K, Inaba J, Yoshimi A, Takahashi Y, Kudo K, Kato K, Matsuyama T. Long-term outcome of acquired aplastic anaemia in children: comparison between immunosuppressive therapy and bone marrow transplantation. Br J Haematol 2000; 111 : 321-328.
4. Fuhrer M, Burdach S, Ebell W, Gadner H, Haas R, Harbott J et al. Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience. German/Austrian Pediatric Aplastic Anemia Working Group. Klin Padiatr 1998; 210 : 173-179.
5. Horowitz MM. Current status of allogeneic bone marrow transplantation in acquired aplastic anemia. Semin Hematol 2000; 37 : 30-42.
6. Bacigalupo A, Brand R, Oneto R, Bruno B, Socie G, Passweg J, Locasciulli A et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy-The European Group for Blood and Marrow Transplantation experience. Semin Hematol 2000; 37 : 69-80.
7. Ohara A, Kojima S, Hamajima N et al. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood 1997; 90 : 1009-1101.
8. Margolis DA, Casper JT. Alternative-donor hematopoietic stem-cell transplantation for severe aplastic anemia. Semin Hematol 2000; 37 : 43-55.
9. Kojima S, Ohara A, Tsuchida M, Kudoh T, Hanada R et al Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood 2002; 100 : 786-790.
10. Ohbayashi Y, Nagai M, Sasaki K, Murata M, Tasaka T, Kubota Y, et al. Acute monocytic leukemia following anti-lymphocyte immunoglobulin treatment in a patient with severe aplastic anemia. Rinsho Ketsueki (Japanese) 1993; 34 : 673-675.
11. Yoshihara T, Morimoto A, Itoi T, Nakagawa M, Kawakatsu H, Todo S et al. An adolescent case of myelodysplastic syndrome following aplastic anemia. Rinsho Ketsueki (Japanese) 1989; 30 : 78-83.
12. Socie G, Henry-Amar M, Bacigalupo A et al. Malignant tumors occurring after treatment of aplastic anemia. N Engl J Med 1993; 29 : 1152-1157.
13. Kaminsky ER, Hows JM, Goldman JM, Batchelor JR. Pretransfused patients with severe aplastic anaemia exhibit high numbers of cytotoxic T lymphocyte precursors probable directed at non-HLA antigens. Br J Haematol 1990; 76 : 401-405.
14. Killick SB, Win N, Marsh JC, Kaye T, Yandle A, Humphries C, et al. Pilot study of HLA alloimmunisation after transfusion with pre-storage leuco-depleted blood products in aplastic anaemia. Br J Haematol 1997; 97 : 677-684.(Bakhshi Sameer, Gupta Aja)
Abstract
Severe aplastic anemia (AA) is a life-threatening condition wherein bone marrow transplantation (BMT) is the therapy of choice in a young patient who has a matched sibling donor. Here, we report an 11-year-old boy with severe AA who was referred for BMT late in its course when he had developed acute myeloid leukemia following two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin. He was then treated with induction therapy using cytosine arabinoside and daunomycin for acute myeloid leukemia, but he succumbed due to infection and refractory leukemia. We discuss the relevance of early referral for BMT in severe AA.
Keywords: Aplastic anemia; Bone marrow transplantation; Immunosuppressive therapy; Leukemia
Aplastic anemia (AA) is a potentially life-threatening failure of hemopoiesis characterized by pancytopenia and bone marrow aplasia. Classification of AA depends on degree of peripheral blood pancytopenia. Severe AA is defined by bone marrow cellularity < 25% and very low values of at least 2/3 hemopoietic lineages: absolute neutrophil count (ANC) < 500/mm 3, platelet count <20,000/mm 3, and reticulocyte count <60,000/mm. 3 Very severe AA meets the same criteria except that ANC < 200/mm. 3 The 2-year mortality rate with supportive care in severe or very severe AA is 80% with invasive fungal infections, bacterial sepsis and bleeding manifestations being the most common cause of death.[1],[2] The current modalities of treatment for severe AA include immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporin or allogenic matched-sibling bone marrow transplantation (BMT). Although IST may result in a response rate of > 70% in severe AA, patients are not considered cured because of high rates of relapse and development of clonal disease[3],[4]. Here, we report a case of severe AA who was referred for BMT late in its course and discuss the relevance of early referral for BMT in this condition.
Case Report
An 11-year-old boy, a known case of severe AA was referred for BMT after having failed two courses of IST. He was initially treated with treated with antilymphocyte globulin and cyclosporin in December 1999 at an outside hospital; cyclosporin was continued till April 2003. Two months after stopping cyclosporine, his counts started falling and cyclosporin was reintroduced but there was poor response. He was then given a repeat course of ATG and cyclosporine in November 2003 without any response. His HLA matching was done and he showed identical match with his elder sister. Studies for paroxysmal nocturnal hemoglobinuria (PNH) were normal. He was referred in April 2004 for allogenic BMT. Physical examination revealed a febrile patient with marked pallor, gum hypertrophy, left orchitis and hepatosplenomegaly of 2 cm each. Investigations revealed hemoglobin 6g/dL, platelet count 40,000/mm 3, white blood cell count 67,200/mm 3; peripheral smear showed 37% myeloblasts. Bone marrow examination confirmed a diagnosis of acute monocytic leukemia (AML-M5); bone marrow cytogenetics revealed normal male karyotype with no evidence of any abnormality. His chest radiograph revealed right lower lobe pneumonitis with pleural effusion.
He was treated with intravenous antibiotics and amphotericin B. Fever subsided and he was started on 3 + 7 induction therapy (daunomycin 60 mg/m 2sub infusion daily for three days and cytosine arabinoside 100 mg/m 2 for seven days as continuous infusion). There was recurrence of fever during induction with evidence of chest infection. CT chest done revealed right side loculated effusion, consolidation in the left upper lobe and bilateral lower lobes along with small pretracheal and left hilar nodes. On this basis, antitubercular therapy was started in addition to antibiotics and antifungal therapy. Day 22 marrow was not in remission and showed 40% blasts. He was then started on reinduction with daunomycin (50 mg/m2 for 3 days), cytosine arabinoside (100 mg/m 2sub every 12 hourly intravenous push for 10 days) and etoposide (100 mg/m 2sub for 5 days). However, the patient developed progressively worsening pneumonia unresponsive to antimicrobial therapy. The child died of septicemia, pneumonia and disseminated intravascular coagulation.
Discussion
The decision for type of treatment (BMT or IST) depends on age of patient, severity of AA and type of allograft (matched sibling or matched unrelated donor). HLA-matched sibling transplant is treatment of choice in young patients (<40 years) with severe AA.[1],[2] However, only 30 % patients have a matched sibling donor. In patients < 30 years of age, cure rates of 70% to 90% are achieved with HLA-matched sibling BMT donor.[5] Since a matched donor was available, an allogenic BMT should have been the treatment of choice in our case.
European BMT registry data suggested that ANC and patient age are predictors of outcome for BMT and IST. BMT is superior to IST in children regardless of ANC and adults up to 40 yrs with low ANC < 300/mm.[3] IST is superior in adults more than 40 years of age and either BMT or IST may be appropriate in patients aged 10-40 years with ANC >300/mm.[5],[6] However, there is a higher risk of late death in patients treated with IST owing to relapse of AA, MDS, acute leukemia or PNH.[7] BMT using matched unrelated donors or mismatched donors is reserved for patients failing IST.[8]
IST is used in patients who are not candidates for BMT. Response to ATG occurs in 50% by 3 months and 75% by 6 months. Some patients are cyclosporine sensitive and require longer course of cyclosporine and also a very slow tapering. Relapse occurs in 30% when cyclosporin is stopped at 6 months. 15% of children and adults with acquired AA develop MDS or associated AML after IST.[7],[9] Whether this is treatment related or due to longer survival after IST allowing time for these underlying clones to expand is not clear. Even before IST, 5% patients showed progression to clonal hemopoiesis[7]. These patients with MDS/AML show chromosome 5, 7 or 8 abnormalities; monosomy 7 is the most common anomaly. Reports of evolution of AA into acute monocytic leukemia are also known, which may be either therapy-related or following a period of MDS[10],[11].
In a study, 12/113 patients children with AA treated with IST developed MDS/AML at 9-81 months following diagnosis; number of days of G-CSF therapy and nonresponse to IST at 6 months being significant risk factors.[9] Socie' et al analyzed 860 patients of severe AA who received IST and 748 patients who received BMT. 42 malignant conditions were reported in 860 patients who received IST: 19 cases of MDS, 15 cases of acute leukemia, 1 case of non-Hodgkin's lymphoma and 7 solid tumors. On the other hand, only 9 were reported in 748 patients who received BMT: 2 cases of acute leukemia and 7 solid tumors.[12]
A common problem in multi-transfused patients with AA compared with leukemia patients is that they may develop alloimmunization to leucocytes present in red cell and platelet transfusions by generating HLA or non-HLA (minor histocompatibility) antibodies. This can result in platelet refractoriness, as well as an increased risk of graft rejection after allogenic BMT.[13] In a retrospective study, incidence of HLA alloimmunization was reported to be 50% in patients with AA who had received blood products prior to introduction of prestorage leucocyte depletion in UK compared with 12% for patients who received only leucocyte-depleted blood products.[14]
Thus, young patients with severe AA should undergo HLA matching at the time of diagnosis and if HLA match is available they should be given the option of BMT. This is especially important as outcome of BMT is significantly better if it is done early rather than late in course of the disease before being multi-transfused and development of clonal disease.
References
1. Brodsky RA, Jones RJ. Aplastic Anemia . Lancet 2005; 365 : 1647-1656.
2. Marsh JC. Management of acquired aplastic anaemia. Blood Rev 2005; 19 : 143-151.
3. Kojima S, Horibe K, Inaba J, Yoshimi A, Takahashi Y, Kudo K, Kato K, Matsuyama T. Long-term outcome of acquired aplastic anaemia in children: comparison between immunosuppressive therapy and bone marrow transplantation. Br J Haematol 2000; 111 : 321-328.
4. Fuhrer M, Burdach S, Ebell W, Gadner H, Haas R, Harbott J et al. Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience. German/Austrian Pediatric Aplastic Anemia Working Group. Klin Padiatr 1998; 210 : 173-179.
5. Horowitz MM. Current status of allogeneic bone marrow transplantation in acquired aplastic anemia. Semin Hematol 2000; 37 : 30-42.
6. Bacigalupo A, Brand R, Oneto R, Bruno B, Socie G, Passweg J, Locasciulli A et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy-The European Group for Blood and Marrow Transplantation experience. Semin Hematol 2000; 37 : 69-80.
7. Ohara A, Kojima S, Hamajima N et al. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood 1997; 90 : 1009-1101.
8. Margolis DA, Casper JT. Alternative-donor hematopoietic stem-cell transplantation for severe aplastic anemia. Semin Hematol 2000; 37 : 43-55.
9. Kojima S, Ohara A, Tsuchida M, Kudoh T, Hanada R et al Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood 2002; 100 : 786-790.
10. Ohbayashi Y, Nagai M, Sasaki K, Murata M, Tasaka T, Kubota Y, et al. Acute monocytic leukemia following anti-lymphocyte immunoglobulin treatment in a patient with severe aplastic anemia. Rinsho Ketsueki (Japanese) 1993; 34 : 673-675.
11. Yoshihara T, Morimoto A, Itoi T, Nakagawa M, Kawakatsu H, Todo S et al. An adolescent case of myelodysplastic syndrome following aplastic anemia. Rinsho Ketsueki (Japanese) 1989; 30 : 78-83.
12. Socie G, Henry-Amar M, Bacigalupo A et al. Malignant tumors occurring after treatment of aplastic anemia. N Engl J Med 1993; 29 : 1152-1157.
13. Kaminsky ER, Hows JM, Goldman JM, Batchelor JR. Pretransfused patients with severe aplastic anaemia exhibit high numbers of cytotoxic T lymphocyte precursors probable directed at non-HLA antigens. Br J Haematol 1990; 76 : 401-405.
14. Killick SB, Win N, Marsh JC, Kaye T, Yandle A, Humphries C, et al. Pilot study of HLA alloimmunisation after transfusion with pre-storage leuco-depleted blood products in aplastic anaemia. Br J Haematol 1997; 97 : 677-684.(Bakhshi Sameer, Gupta Aja)