Sustained long-term complete remission in an elderly aplastic anemia patient after cessation of combined therapy consisting of granulocyte-colony stimulating factor and erythropoietin

An 83-year-old woman received a diagnosis of moderate aplastic anemia in November 1990. Immunosuppressive therapy consisting of anti-lymphocyte globulin combined with high-dose corticosteroids was effective until pancytopenia developed in August 1993. The patient was hospitalized again and recurrence of aplastic anemia was diagnosed on the basis of hematologic findings, including RBC 129 x 10(4)/microliter, Hb 5.5 g/dl, Ret 23,200/microliter, WBC 2,200/microliter with 27% neutrophils, platelets 2.2 x 10(4)/microliter, and hypoplastic bone marrow. Recombinant human granulocyte-colony stimulating factor (G-CSF) of 125 micrograms/day combined with recombinant human erythropoietin (EPO) of 6,000 U/day were started in November 1993. The doses of G-CSF and EPO were increased to 250 micrograms/day and 12,000 U/day, respectively. We stopped combination therapy in March 1995, after trilineage hematopoietic cell recovery had been achieved. Complete recovery in peripheral blood was sustained for more than 2 years despite the termination of G-CSF and EPO therapy. Combination therapy with G-CSF and EPO may be safe and effective for elderly patients with aplastic anemia when the choice of therapy is limited.     

Aplastic anemia successfully treated with erythropoietin and rhG-CSF]

A 32 year-old female admitted to our hospital with pancytopenia. The hematological data on admission were: RBC: 247 x 10(4)/microliters, Hb: 8.8 g/dl, Plts: 13,000/microliters, WBC: 2,500/microliters. Bone marrow aspirate and biopsied specimen showed marked hypocellularity without infiltration of abnormal cells. A diagnosis of aplastic anemia was made. Neither high-dose methyl-prednisolone pulse therapy nor anti-lymphocyte globulin were effective. With combination of oxymetholone (30 mg/day), recombinant erythropoietin (rHuEpo; 12,000 U/day, three times a week) and recombinant granulocyte-colony simulating factor (rHuG-CSF; 33 micrograms/day) for 3 months, remarkable improvements of hematological data were obtained. Her hemoglobin level reached 11.4 g/dl, and platelets count 49,000/microliters. However, 4 weeks after the withdrawal of erythropoietin and G-CSF administrations, her platelet count fell to 12,000/microliters. It was suggested that combination therapy with erythropoietin and G-CSF were effective for aplastic anemia.     

Severe aplastic anemia successfully treated with cyclosporin A and prednisolone

A 7-year-old boy was admitted to our department complaining pale face and subcutaneous bleeding in August, 1987. Peripheral blood analysis showed pancytopenia of WBC 2,600/microliter, RBC 148 x 10(4)/microliter and platelets 5,000/microliter. Bone marrow biopsy revealed hypocellularity. Granulocytes 104/microliter, reticulocytes 4,290/microliter and platelets 5,000/microliter were compatible with the diagnosis of severe aplastic anemia based on the criteria of the Ministry of Public Welfare in Japan. Prednisolone (PDN) was initially indicated and bolus methylprednisolone, metenolone and ALG therapy followed with no hematological improvement. Fifteen months after admission, in addition to 0.5-1 mg/kg/day of metenolone, Cyclosporin A (CyA) was started at a dose of 12 mg/kg/day for a week and 6 mg/kg/day thereafter. After a week from administration of CyA, 1 mg/kg/day of PDN was given because his bleeding tendency became worse. But this combination was complicated with liver damage and hyperglycemia to discontinue both drugs. These adverse effects were subsided within 7 days by cessation of the drugs. CyA was started again at a dose of 6 mg/kg/day without any response for 4 weeks. Then PDN was added together at a reduced dose of 0.5-1 mg/kg/day. Hematological response was obtained promptly. Granulocytes reached 1,500/microliter, hemoglobin 10.2 g/dl and platelets 26,000/microliter after 3 months of therapy. Afterward the patient became transfusion independent. The most effective method of CyA administration for aplastic anemia is still controversial. Alternative use of CyA, considering combination of steroids or anabolic steroids, in patients who failed to respond to conventional immunosuppressive treatments should be further investigated.     

Successful treatment of idiopathic pure red cell aplasia with antithymocyte globulin]

An 18-year-old woman was admitted to our hospital because of severe anemia on October 16, 1999. Laboratory data included hemoglobin 3.5 g/dl, reticulocytes 2,200/microliter, WBC 3,500/microliter, and Plt 38.5 x 10(4)/microliter. Bone marrow aspiration showed a normocellular marrow with severe erythroid hypoplasia, suggesting a diagnosis of pure red cell aplasia. Methylprednisolone pulse therapy was started on October 20, but there was no response. Administration of cyclosporine A (CyA; 400-450 mg) was begun on November 1, but again there was no response. Antithymocyte globulin (ATG; 800 mg/day for 5 days, 15 mg/kg) was started from December 1 in addition to prednisolone (60 mg/day) and CyA (450 mg/day). On day 7 of ATG therapy, the reticulocyte count began to increase, and reached a peak of 32.6 x 10(4)/microliter on day 20. The patient's hemoglobin level started to increase on day 13, and reached 8.5 g/dl on day 27. A complete response has been maintained up to the time of writing, and the hemoglobin level was 11.9 g/dl on December 14, 2000. This is the first detailed Japanese case report of successful treatment of pure red cell aplasia using ATG.     

Requirements of diagnostic criteria for aplastic anemia in children]

As a general rule, diagnostic criteria of aplastic anemia in children are the same as adult criteria. However, blood counts of normal children show wide age-related variation, therefore we must establish a system of adjustment for diagnosis of aplastic anemia in children. The data of children with aplastic anemia visiting our institutes from 1966 to 1990 were evaluated for this study. RBC below 350 x 10(4)/microliters, WBC below 4,000/microliters or neutrophils below 1,500/microliters, platelets below 8 x 10(4)/microliters, reticulocytes below 4 x 10(4)/microliters and lymphocytes over 60% were seemed to satisfy the diagnostic criteria of aplastic anemia proposed by the Study Group of hemopoietic Disorders sponsored by the Ministry of Health and Welfare of Japan. Fifteen children (4.6%) did not meet these criteria and as such were diagnosed as atypical aplastic anemia. Thirteen of them were in a pre-aplastic state and developed typical aplastic anemia within 6 months to 8 years after the initial diagnosis. Clinical findings of these patients showed the decrease in number of megakaryocytes and committed stem cells in bone marrow. Three of these patients developed acute non-lymphocytic leukemia, and 2 of them were diagnosed as Fanconi's anemias.     

Congenital stomatocytosis associated with aplastic anemia

A seven year-old boy with hereditary stomatocytosis complicated with aplastic anemia was reported. He was admitted to our hospital because of pale and general fatigue. On physical examination, he had severe anemia, petechiae, but no hepatosplenomegaly. Peripheral blood cell count revealed pancytopenia; RBC 103 X 10(4)/microliters, Hb 3.5 g/dl, Ret 21%, WBC 1,200/microliters, Pl 1.3 X 10(4)/microliters, and bone marrow revealed markedly hypocellular marrow. Red cell morphology demonstrated stomatocytosis. Red cell life span (51Cr T1/2) was 12 days, Coombs' test and Ham's test were negative. Indirect bilirubin was 1.1 mg/dl and marked decrease of haptoglobin was found. Family studies showed that his father and sister had stomatocytosis on peripheral blood examination, but no anemia. The patient had severe anemia because of complicated aplastic anemia. Congenital stomatocytosis with aplastic anemia is extremely rare. The authors are interested in a possible relationship between hereditary stomatocytosis and aplastic anemia although the precise mechanism remains to be elucidated.     

Remarkable improvement of anemia by administration of recombinant human erythropoietin in a patient with aplastic anemia

A 69-year-old female was admitted for pancytopenia. The hematological examination showed leukocytes 1,800/microliters, hemoglobin 5.3 g/dl and platelets 9.6 x 10(4)/microliters. A bone marrow aspiration revealed hypoplasia, but no abnormal cells. Serum erythropoietin titer was 5,100 mU/ml. Diagnosis of aplastic anemia was made. She received 400 ml of blood transfusion twice, and was then treated with recombinant human erythropoietin (rHuEPO) (12,000 U/day) three times a week for eight weeks. Hemoglobin level gradually increased to the level of 12.0 g/dl. This case suggests that there are some cases of aplastic anemia which can respond to treatment with rHuEPO.     

Two cases of orbital non-Hodgkin's lymphoma presenting with hemophagocytic syndrome

We report 2 cases of orbital non-Hodgkin's lymphoma (NHL) with hemophagocytic syndrome (HPS). Patient 1 was a 64-year-old man with a diagnosis of peripheral T-cell lymphoma originating in the right orbita (clinical stage: IV B). Epstein-Barr virus DNA was demonstrated in tissue specimens by polymerase chain reaction. Laboratory findings on admission were WBC: 4,700/microliter, Hb: 12.1 g/dl, Plt: 14.6 x 10(4)/microliter, LDH: 951 IU/l, sIL-2R: 2,553 IU/ml, and ferritin: 5998.1 ng/ml. Patient 2 was a 73-year-old man with a diagnosis of diffuse large B-cell lymphoma originating in the right orbita (Clinical stage: IV B). Laboratory findings on admission were WBC: 9,100/microliter, Hb: 7.7 g/dl, Plt: 15.4 x 10(4)/microliter, LDH: 1,043 IU/l, sIL-2R: 10,090 IU/ml, and ferritin: 2079.3 ng/ml. Both patients had high-grade fever and extremely high serum cytokine levels. Bone marrow aspiration disclosed many histiocytes with hemophagocytosis. In both cases, combined chemotherapy was transiently effective, but patient 1 died of relapse of HPS and patient 2 of cerebral bleeding. Orbital non-Hodgkin's lymphoma with HPS is rare. These cases were interesting in terms of the relationship between HPS and the primary site of lymphoma.     

Leukocytopenia and thrombocytopenia preceded by human parvovirus B19 infection: report of three adult cases

In Saiki City, Oita, Japan, erythema infectiosum in children has been prevalent from June, 1999 to the time of writing (January, 2000). We present three adult cases of parvovirus B19-associated leukocytopenia and thrombocytopenia that developed during this epidemic. Between June and November, 1999, a 32-year-old woman, a 38-year-old woman, and a 63-year-old man were referred to our hospital for treatment of leukocytopenia and thrombocytopenia. All complained of common cold-like symptoms. Their WBC counts (percentage of neutrophils) were 1,000/microliter (70%), 1,900/microliter (40%) and 1,680/microliter (40%), their hemoglobin levels 9.4 g/dl, 9.8 g/dl and 14.9 g/dl, and their platelet counts 10.8 x 10(4)/microliter, 6.9 x 10(4)/microliter and 4.5 x 10(4)/microliter, respectively. The diagnosis of parvovirus B19 infection was documented by the presence of B19-specific IgM antibodies or serum positivity for viral DNA. In two cases, the leukocytopenia and thrombocytopenia resolved gradually. In the other case, leukocytopenia, thrombocytopenia and B19 infection persisted for more than two months. These cases suggest that parvovirus B19 may be a common cause of leukocytopenia and thrombocytopenia even in adult patients without hematological disorders (erythropoietic stress), and that testing for parvovirus infection is justified in such patients, even if anemia is slight, especially when erythema infectiosum is prevalent.     

Fulminant autoimmune hemolytic anemia with multiple organ failure

We report a rare case of fulminant autoimmune hemolytic anemia (AIHA) with multiple organ failure (MOF). A 40-year-old man was emergently admitted to our hospital because of conscious disturbance and jaundice. The peripheral blood revealed RBC 68 x 10(4)/microliter, Hb 3.5 g/dl, Ht 8.9%, Ret 30% (20,400/microliter), WBC 20,300/microliter, Plts 16.9 x 10(4)/microliter, indirect bilirubin 9.4 mg/dl. Both direct and indirect Coombs test were positive and the IgG autoantibody was identified. Bone marrow aspiration revealed hypercellularity with increased megakaryocytes and erythroid hyperplasia. The patient was diagnosed as having idiopathic warm type of AIHA and the therapy was started with prednisolone 80 mg/day from the first day of admission but hemolysis with reticulocytopenia was so rapidly progressive that he was in acutely life-threatening state and MOF (acute renal failure, adult respiratory distress syndrome, congestive heart failure, liver dysfunction, rhabdomyolysis) appeared on the third hospital day. Plasma exchange therapy and hemodialysis were started and high dose methylprednisolone was given soon after rapid administration of sufficient blood transfusion. Dramatic improvement of hemolysis was noted and MOF was controlled after starting these therapies, but he died of exacerbation of MOF probably due to sepsis 40 days later.     

IBL-type lymphadenopathy after infection of rubella virus]

A 52-year-old woman presented slight fever, diffuse papular skin rash and painful cervical lymph node swelling. Her lymph node swelling generally up to 3 cm in diameter, with petechiae on the lower legs and hepato-splenomegaly within a few weeks. ESR was 45 mm/h, Hb 10.0 g/dl, RBC 345 x 10(4)/microliter, WBC 22,600/microliter (atypical lymphocyte 47%), PLT 1.0 x 10(4)/microliter, GPT 91 U/L, gamma-globulin 34.3%, EBV-VCA x 2,560, EBNA x 20, and anti-rubella antibody x 512. The biopsied cervical lymph node showed histologic features of effacement of nodal architecture by an exuberant vascular proliferation accompanied with infiltration of the immunoblasts, and was diagnosed as immunoblastic lymphadenopathy (IBL)-type lymphadenopathy. The pulse therapy of methylprednisolone and high dose of gamma-globulin improved lymphadenopathy, thrombocytopenia and anemia. IBL-type lymphadenopathy after infection of rubella virus may be different from true IBL, but is important to discuss the pathogenesis of IBL.     

Neutrophil dysfunction in chronic neutrophilic leukemia without rearrangements of bcr and immunoglobulin heavy chain genes

A 67-year-old man was admitted to our hospital with abdominal distension due to hepatosplenomegaly. The peripheral blood revealed Hb content 6.5 g/dl, platelet count 4.7 x 10(4)/microliter, and WBC count 105.8 x 10(3)/microliter with 88% of mature neutrophils. The neutrophil alkaline phosphatase score was 421. Bone marrow aspiration revealed hypercellularity with increased megakaryocytes and myeloid hyperplasia. 46, XY, del 20(q 11) without Philadelphia chromosome was identified by cytogenetic study. The patient was diagnosed as having chronic neutrophilic leukemia and was successfully treated with busulfan, but he died of atypical mycobacteriosis about 20 months later. Analysis of neutrophil function demonstrated diminution of deformability, random mobility, and chemotaxis, but almost normal phagocytosis and bactericidal capacity. Southern analysis showed no rearrangements of breakpoint cluster region (bcr) gene and immunoglobulin heavy chain gene.     

Methimazole-induced aplastic anemia caused by hypocellular bone marrow with plasmacytosis.

Aplastic anemia is a rare but severe complication of methimazole (MMI) treatment for Graves' disease. We present a case of a 53-year-old Japanese female who had been treated with 30 mg/d of MMI for 30 days for Graves' disease and was subsequently admitted to the Japan Self Defense Forces (JSDF) Central Hospital with a mild sore throat and high-grade fever that began the previous day. The patient had a reduced white blood cell count (WBC) count of 0.9 x 10(3) per microliter with severe granulocytopenia and increased lymphocytes, a platelet count of 49 x 10(3) per microliter, and hemoglobin of 10.6 g/dL. Bone marrow (BM) aspirates showed hypocellular bone marrow with plasmacytosis. Because of poor recovery of her peripheral blood values after withdrawal of MMI, she was given transfusions of platelets and erythrocytes thereafter. This is the second report of plasmacytosis in bone marrow of MMI-induced aplastic anemia, and suggests that immunogenic mechanisms may cause this rare complication.     

Myelodysplastic syndrome in a patient with familial Pelger-Huet anomaly]

This paper reports on a patients with congenital Pelger-Huet anomaly who developed myelodysplastic syndrome (MDS). A 45-year-old female was referred for investigation of pancytopenia of 6 months' duration. Hereditary Pelger-Huet anomaly was diagnosed by family study 7 years prior to admission. On admission, Hb was 6.5 g/dl, Ht 19.9%, Platelets 1.8 x 10(4)/microliters, and WBC 1,200/microliters with 2% myelocytes, 9% metamyelocytes, 14% bands, 2% segmented neutrophils, 58% lymphocytes and 5% monocytes. Most of the granulocytes were Pelger-Huet type with strikingly clumped nuclear chromatin. Bone marrow aspirate demonstrated 3.6% blasts and dysplastic changes including megaloblastoid features in erythroid series and micro-megakaryocytes compatible with refractory anemia, a subtype of MDS. The association of hereditary Pelger-Huet anomaly and MDS is discussed.     

Successful treatment with immunosuppressive therapy for aplastic anemia developed after resection of thymoma

We report here a very severe case of thymoma-related aplastic anemia that developed after thymectomy. The patient was a 50-year-old man diagnosed with myasthenia gravis. Chest CT showed thymoma measuring 7.5 cm in diameter, and extended thymectomy was performed. Irradiation to the anterior mediastinum was added postoperatively. Thirteen months after surgery, hemogram showed severe neutropenia: leukocyte count 0.32×10(9)/l with 11% neutrophils; Hb 10.7 g/dl; and platelet count 100×10(9)/l. Although cyclosporine (CSP, 5 mg/kg/day) was administered, dose reduction was necessary because of renal damage. Cytopenia deteriorated to a leukocyte count of 0.71×10(9)/l with 21% neutrophils; Hb 5.9 g/dl; and platelet count 24×10(9)/l. However, addition of antithymocyte globulin (ATG, 15 mg/kg) led to hematopoietic recovery of all three lineages within one month. He is clinically stable with no transfusion requirement after 22 months with CSP maintenance therapy. Although thymoma-related aplastic anemia has been reported to have an extremely poor prognosis, high efficacy of CSP has been reported recently. In our case, ATG in combination with CSP was efficient. Adequate immunosuppressive therapy seems to be important for the clinical management of these patients.     

Stable Response after Administration of Stem Cell Factor Combined with Granulocyte Colony-Stimulating Factor in Aplastic Anemia

We report successful treatment with 25 microg/kg of recombinant methionyl human stem cell factor (SCF) combined with 400 microg/m2 of recombinant human granulocyte colony-stimulating factor (G-CSF) in 2 patients with aplastic anemia refractory to immunosuppressive therapy. In one patient, hemoglobin levels increased from 6.4 g/dL to 11.3 g/dL after 36 weeks of SCF/G-CSF treatment. Thereafter, the platelet count (24.0 x 10(9)/L) began to improve without the therapy, and as of week 272, the platelet count was 125.0 x 10(9)/L with a leukocyte count of 8.4 x 10(9)/L and a hemoglobin level of 12.9 g/dL. In the other patient, more than 3 years of SCF/G-CSF treatment ameliorated hemoglobin levels and platelet counts from 5.8 g/dL to 15.9 g/dL and 8.0 x 10(9)/L to 50.0 x 10(9)/L, respectively. After cessation of SCF/G-CSF treatment, the positive response was sustained, and the platelet count improved further to 71.0 x 10(9)/L as of week 242. These observations suggest the clinical benefit of SCF/G-CSF administration to patients with refractory aplastic anemia.     

Development of severe aplastic anemia in a girl with Hashimoto's thyroiditis and papillary thyroid carcinoma

A 14-year-old girl was admitted because of general fatigue and cervical lymphadenopathy. She showed bilateral struma (IInd degree) and enlargement of her left cervical lymph nodes. Laboratory data revealed neutropenia (219/microliter) and thrombocytopenia (Plt 5.1 x 10(4)/microliter) with mild anemia (Hb 11.1 g/dl), and the bone marrow aspirate and biopsy specimens showed hypocellularity. In addition, auto-antibodies against thyroid peroxidase (TPO) and thyroglobulin (TG) were highly elevated. Computed tomography of the neck showed a nodule in the left thyroid lobe with marked lymphadenopathy, and fine needle aspiration biopsy demonstrated papillary thyroid carcinoma with Hashimoto's thyroiditis and metastasis to the lymph nodes. One month after left thyroid lobectomy and cervical lymphadenectomy, the patient's condition progressed to very severe aplastic anemia, and she received immunosuppressive therapy consisting of cyclosporin A and anti-thymocyte globulin. Hematologically, partial and complete responses were obtained three and six months later, respectively. Of interest, anti-TPO and TG antibody titers remarkably decreased after immunosuppressive therapy. The patient had HLA-DR 2(DRB 1*1501) and DR 8(DRB 1*0802). The former is frequently found in patients with cyclosporin A-dependent aplastic anemia, and the latter is frequently found in Asian patients with Hashimoto's thyroiditis, suggesting an underlying autoimmune background for the simultaneous outbreak of aplastic anemia and Hashimoto's thyroiditis complicated by thyroid carcinoma.     

An elderly case of idiopathic thrombocytopenic purpura associated with acute myocardial infarction

We report a rare case of idiopathic thrombocytopenic purpura (ITP) associated with acute myocardial infarction (AMI). A 72-year-old woman with hypertension and hemorrhoids was admitted because of chest pain, severe anemia (RBC 340 x 10(4)/microliter, Hb 5.4 g/dl, Ht 21.7%) and thrombocytopenia (0.2 x 10(4)/microliter). AMI was diagnosed by electrocardiogram (ST elevation and negative T in V2-5), echocardiogram (hypokinesis in anteroseptal wall) and laboratory (CPK 470 U/l) findings and was treated with only blood transfusion. Chest pain disappeared the day after admission, and neither heart failure nor arrhythmia occurred. Based on bone marrow findings (hyperplasia of erythroblast and megakaryocyte), endoscopic (internal hemorrhoids) and laboratory (antiplatelet antibody positive, platelet associated IgG 257.8 ng/10(7) cells) findings, iron deficiency anemia and ITP were diagnosed. Anemia improved after blood transfusion, but thrombocytopenia (< 1.0 x 10(4)/microliter) without active bleeding continued after steroid and gamma-globulin therapy. At discharge, electrocardiogram showed a negative T in I, aVL and V2-5, and T1 and BMIPP myocardial scintigram showed defects in the anteroseptal and apical wall.     

Transient myelodysplasia associated with human parvovirus B19 infection in a child without underlying disease]

Human parvovirus B19 (HPV-B19) infection is known to frequently induce aplastic crisis in patients with hemolytic anemia, but rarely causes hematological disorders in healthy subjects. We report a 5-year-old boy who showed transient myelodysplasia associated with HPV-B19 infection. He was admitted with severe nasal bleeding, and laboratory data showed marked thrombocytopenia (1,000/microliter), anemia (Hb: 8.4 g/dl), and mild leukopenia (3,000/microliter). A bone marrow smear revealed myelodysplastic changes in three cell lineages, but no giant proerythroblasts or megakaryocytes. The pancytopenia and myelodysplastic changes were resolved spontaneously within a week without any medication other than transfusion of red blood cells and platelets. Serological examination revealed an elevation of IgG antibody against HPV-B19 on days 15 and 120 and its subsequent decrease thereafter, although HPV-B19-specific DNA was not detected in the serum at onset. The clinical course and laboratory data suggest an etiologic role of HPV-B19 infection in the occurrence of transient myelodysplasia.     

Hepatitis-associated aplastic anemia preceded by a hemophagocytic syndrome-like state

A 21-year-old man was admitted to our hospital for acute hepatitis of unknown cause. His liver function improved with rest, but worsened 2 months later. He developed a high fever and pancytopenia. The serum level of cytokines including TNF-alpha, IFN-gamma, IL-6, and M-CSF was elevated, and hemophagocytes were seen in bone marrow. These findings suggested a hemophagocytic syndrome-like state. With prednisolone, gamma-globulin, and G-CSF, the high fever disappeared and the patient's liver function gradually recovered. However, the severe pancytopenia persisted. The bone marrow became acellular with a small number of hemophagocytes, and hepatitis-associated aplastic anemia was diagnosed. After immunosuppressive therapy with ATG, CyA and G-CSF was started, and the patient showed hematopoietic reconstitution. The bone marrow CD4+/CD8+ lymphocyte ratio recovered to within the normal range, and the serum cytokines including TNF-alpha and IFN-gamma decreased. The increase in serum cytokines, particularly TNF-alpha and INF-gamma, as well as the presence of activated T cells associated with the preceding hemophagocytic syndrome-like state may have predisposed this patient to aplastic anemia.