The immune reactivity of allogeneic lymphocytes plays a major role in control of leukemia after bone marrow transplantation. We studies the efficacy of donor leukocyte transfusion (DLT) on acute and chronic leukemia in relapse after bone marrow transplantation in Japan. Sixty nine patients with chronic myelocytic leukemia (N=17), acute lymphoblastic leukemia (N=25), acute myelocytic leukemia (N=26), myelodysplastic syndrome (N=5), non-Hodgkin lymphoma (N=2) and rhabdomyosarcoma (N=1) were treated with transfusions of donor lymphocytes. Therapeutic effects were induced by donor leukocyte transfusion in 20 patients (29%) including 3 patients out of 4 (75%) with CML in cytogenetic and chronic phase relapse, 4 out of 5 (80%) patients with myelodysplastic syndrome, 3 out of 13 (23%) patients with CML in transformed phase, 5 out of 25 (20%) patients with acute myelocytic leukemia, and 4 out of 20 (20%) patients with acute lymphoblasic leukemia. Twenty two patients (30%) developed acute GVHD (≥2) and 6 out of 73 (8.2%) patients developed fatal GVHD after donor leukocyte transfusion. Patients relapsed within 6 months after marrow transplantation had a probability of having severe acute GVHD (≥2) after DLT. Fourteen out of 24 (58%) patients with GVL response were re-relapsed thereafter. Minimal dose of donor leukocytes infused in successfully treated 9 patients without cytoreductive therapy was 2×10⁷/kg in total and minimal dose of that in 6 patients with fatal GVHD was 7×10⁷/kg in total. The anti-leukemia effect of donor leukocyte transfusion was strongest against CML in cytogenetic and chronic phase and induce a durable complete remission.

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A pharmacokinetic study of all-trans retinoic acid (ATRA) was performed in 8 patients with various types of leukemia and MDS. After oral administration at a dose of 30 mg/m², the mean peak plasma concentration was 430 ng/ml and was reached at 150 min. In one patient who failed to respond a very low plasma ATRA level was seen. Though the plasma ATRA exposure decreased significantly with daily drug administration, an intermittent schedule of ATRA administration would yield higher plasma drug concentrations. We treated 2 patients with refractory acute promyelocytic leukemia (APL) in a pilot study of ATRA followed by intensive chemotherapy (APL-ATRA protocol). Two patients successfully achieved complete remission with ATRA after failing under conventional chemotherapy. Based on the pharmacokinetic study of ATRA, an intermittent schedule of ATRA in addition to chemotherapy suggests an effective regimen for children with APL. Phase II trials to evaluate the role of intermittent schedules of ATRA are planned in Children's Cancer and Leukemia Study Group.

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An intermittent and cyclic regimen with All-Trans Retinoic Acid (ATRA) and intensive chemotherapy was conducted due to pharmacokinetic studies on ATRA for acute promyelocytic leukemia (APL) in children. We have treated 17 children with APL using ATRA for remission induction followed by an intermittent schedule of ATRA plus intensive chemotherapy (APL-ATRA protocol). There were 10 males and 7 females. The median age was 9.0 years old. The median baseline white blood cell count was 12.1×10³/μl, hemoglobin 7.8 g/dl, platelet 4.5×10⁴/μl at diagnosis. Sixteen patients showed t(15;17) translocation. RT-PCR analysis was available in 15 patients and showed PML/RAR α rearrangement in all patients. Overall, 13 of 17 newly diagnosed patients (88%) achieved complete remission and EFS was 67%. Compared to the control (same chemotherapy without ATRA regimen), remission induction and EFS were significantly increased. The toxicity of ATRA consisted of retinoic acid syndrome in 1 and pseudotumor cerebli in another. Other toxicites included headache, chelitis, gastrointestinal trouble and bone pain. These results suggest that intermittent and cyclic regimen with ATRA and intensive chemotherapy (APL-ATRA protocol) is highly effective for APL patients.

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Bone marrow transplantation was performed with a conditioning regimen including antithymocyte globulin (ATG) for 8 patients with HLA-compatible unrelated donors or HLA mismatched donor. Administration of ATG was halted due to side effects in only 1 case. but the other cases were had no adverse reaction. During administration of ATG, platelet counts did not decrease rapidly, but platelet infusion was not effective in some cases. As compared between patients with conventional allogeneic BMT, autologous BMT or peripheral blood stem cell transplantation and those with ATG administration, no obvious difference was seen between the two groups in lymphocyte counts, CD3, CD4, CD8 and CD20 positive cells. No patient with ATG saffered graft failure or acute GVHD. However, cytomegalovirus infection was observed more frequently than in patients without ATG. In hematological malignancy, relapse was more frequent than in patients without ATG.

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A 88-year-old male patinet with G-CSF producing renal cell carcinoma is reported. The patient was admitted to our hospital complaining of macrohematureia. The laoboratory examination showed marked leukocytosis of 18,200/μl (neutrophil 92%) in the peripheral blood and high levels of G-CSF (120 pg/ml) in the serum. An abdominal CT scan revealed a right renal tumor. The neutrophil count rose to 38,700/μl with increasing of tumor size. Histopathological diagnosis was renal cell carcinoma (Grade 3) and immunohistochemical staining using Histo anti-G-CSF antibody demonstrated cancer cells prodcuced G-CSF. This is the second case of G-CSF producing renal cell carcinoma diagnosed by immunohistochemical staining in the literature.

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We report a 82-year-old woman with adult onset Still's disease (AOSD), who presented with high fever, skin rash, swollen axillary lymph nodes, accelerated erythrocyte sedimentation rate, leukocytosis, abnormal liver function tests, hypoalbuminemia, negative antinuclear antibody and rheumatoid factor, and lack of renal involvement. Disseminated intravascular coagulation (DIC) was also diagnosed on admission. An antipyretic relieved high fever and DIC soon improved. Three years later, AOSD relapsed accompanied by hypercoagulation and hyperfibrinolysis. The patient developed subdural hematoma and DIC due to a brain contusion. High titers of serum soluble adhesion molecules and soluble thrombomodulin were noted on the first episode of DIC. These findings indicated that endothelial cells were damaged in AOSD complicated by DIC.

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A 79-year-old woman was admitted with general fatigue, jaundice and hepatosplenomegaly. Perpheral blood examination showed 8.0 g/dl Hb, 15×10³/μl platelet and 10,490/μl leukocytes with 86% abnormal lymphocytes. Immunophenotypic analysis of abnormal lymphocytes demonstrated CD2(+), CD3(±), CD4(-), and CD8(-). Serum antibody for HTLV-1 was positive. In addition, the monoclonal integration of HTLV-1 proviral DNA into the genome of leukemic cells was demonstrated on Southern blot hybridization. Bone marrow revealed ATL cell in vasion with myelofibrosis and hemophagocytic cell proliferation. Therefore, adult T-cell leukemia with hemophagocytic syndrome was diagnosed. She was treated with methyl prednisolone pulse therapy and gammaglobulin. But she died of hepatic failure 14 days after hospitalization. On autopsy, EB virus LMP-1 was detected in ATL cells in bone marrow. ATL with hemophagocytosis is relatively rare. The association of both pathological states was discussed.

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A 69-year-old woman with pure red cell aplasia and granular lymphocytic leukemia was reported. Because her granular lymphocyte count was in the normal range at the time of admission, we diagnosed the patient as primary pure red cell aplasia (PRCA). The granular lymphocyte count increased slowly, and we find monoclonal T cell receptor rearrangement, the case was diagnosed as granular lymphocytic leukemia accompanied with PRCA. Although single administration of cyclosporin or cyclophosphamide induced severe side effects obfained combined administration of low doses of these agents obtained good Hb increase. This case was granular lymphocytic leukemia with normal granular lymphocytic count at the time of diagnosis, the tumor cell suppressed BFU-E colony formation, and combined administration of low dose CPM and CyA yielded good effects.

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A 68 year-old-man was first found to have CLL with IgG, κ monoclonal gammopathy 6 years ago. Bestrabucil (total dose 35,150 mg) was taken orally from August 1989 to December 1989. Etoposide (total dose 23,100 mg) was then orally administered from January 1990 to December 1995. He was then referred to our hospital in January 1996 because of progressive anemia and thrombocytopenia. Peripheral blood showed a WBC of 21,200/μl with 4% myeloblasts and 79% lymphocytes, Hb 7.9 g/dl and Plt 5×10⁴/μl. The serum level of lysozyme was increased (75.6 μg/ml). Bone marrow aspiration disclosed hyper-cellularity with proliferation of the blasts and a monocytoid cell population, which cytochemical studies demonstrated to be of the myelo-monocytic series, thus indicating acute myelogenous leukemia (AML-M4) superimposed on CLL. Surface marker analysis of bone marrow mononuclear cells revealed reactivity for CD 11c, CD13, CD15, CD33, HLA-DR. The karyotype was normal. Southern blot analysis and reverse transcriptase-polymerase chain reaction did not reveal rearrangement of the MLL gene. Complete remission was achieved by chemotherapy consisted of BHAC, idarubicine, 6MP, vincristine and predonisolone. Long-term treatment with oral etoposide may contribute to secondary AML.

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The osseous manifestation of multiple myeloma is well known as the osteolytic or osteoporotic feature. On the other hand, there are rare cases of general osteosclerotic manifestation as myeloma variants. We report a case of multiple myeloma with solitary osteosclerotic legion in the cervical vertebra. A 60-year-old-man was admitted with paralysis of both arms. The cervical roentogenogram showed the osteosclerotic change of the seventh cervical vertebra. The pathological study of surgical bone biopsy from the vertebra revealed osseous and severe fibrotic change and accumulation of plasma cells in the residual bone marrow. Clusters of plasma cells were also observed in the bone marrow of ileac bone. In addition, IgG-λ type M protein was seen in the serum. Therefore we diagnosed this case as the osteosclerotic multiple myeloma. We then analyzed the cytokines known to influence bone formation, and found that the bone marrow serum TGF-β and PDGF levels were increased compared with normal control. These results may suggest that the preferential increase of osteosclerotic cytokines caused the osteosclerotic changes of bone marrow.

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A 84-year-old man was admitted with diabetes mellitus, hypertension and chronic renal failure in September 1994. In October 1995, his renal function gradually worsened with hyperkalemia. Sodium polystyrene sulfonate (Kayexalate) was administered orally for the treatment of hyperkalemia. However, after 7 days from the start of Kayexalate therapy, thrombocytopenia progressed gradually, and 12 days later the initial platelet count of 20.7×10⁴/μl decreased to 8.6×10⁴/μl. This thrombocytopenia rapidly improved after cessation of Kayexalate administration. In December 1995, readministration of Kayexalate for the treatment of hyperkalemia induced thrombocytopenia again. Bone marrow aspiration biopsy revealed normal counts of nucleated cells and megakaryocytes with no increase in blasts. No other disorders which cause thrombocytopenia were seen in this patient. The complication of thrombocytopenia associated with Kayexalate has not been reported. This is the first reported case of thrombocytopenia caused by Kayexalate administration.

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We report a 1-year-old boy with infantile lymphoblastic leukemia in first complete remission who received a cord blood stem cell transplantation (CBSCT) from an HLA indentical sibling. We collected 120 ml of cord blood when his brother was born, which contained 4.2×10⁸ mononuclear cells (4.2×10⁷/kg) and 3.1×10⁵ CFU-GM (3.1×10⁴/kg). One month prior to transplantation, he showed persistent fever and liver dysfunction, and was finally diagnosed as having primary cytomegalovirus (CMV) infection which was demonstrated by elevation of serum anti-CMV-IgM. The administration of ganciclovir dramatically improved the clinical symptoms and abnormal laboratory findings, and was continued up to 1 month after transplantation to suppress the CMV reactivation. The preconditioning regimen consisted of busulfan (16 mg/kg/4days) and cyclophosphamide (120 mg/kg/2days), and cyclosporin A (CyA) alone was used for graft-versus-host disease (GVHD) prophylaxis. Fever suspicious of grade I GVHD developed on day 19, but subsided by increasing the dose of CyA. The WBC and platelet counts reached greater than 1,000/μl and 50×10³/μl on days 12 and 42, respectively. It is now at 13 months since transplantation, and he remains in a disease free state.

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A 62-year-old man was found to have myelodysplastic syndrome (MDS) and gastric cancer. Serum studies revealed hypogammaglobulinemia, and positive reactions to rheumatoid test and anti-nuclear antibody. Chromosomal analysis of the bone a mrrow revealed deletions of No. 5 and 7 chromosomes and that of the stomach showed complex abnormalities. It may be hypothesized that an initial event which selects a clone of stem cells could manifest with this sort of immunological abnormalities. Subsequent deranged immunosurveillance may be responsible for the increased risk of cancer. Alternatively an increased chromosomal instability which seems to be associated with immunodeficiencies might be responsible for cancer development.

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A 61-year-old man was admitted in March 1996 complaining of erythroderma, and Sézary syndrome was diagnosed. The leukocyte count was 33,590/μl with 70.9% abnormal lymphocytes expressing two different types of antigenicity, either CD4+/CD8- (44.5%) or CD4-/CD8+ (48.9%). Clonal T-cell receptor β rearrangement was not found on Southern blot analysis. He suffered repeated sepsis dueto methicillin-resistant Staphylococcus aureus. Combination chemotherapy was not effective for erythroderma and organomegaly, and deoxycoformycin revealed a transient effect. He died of MRSA enterocolitis in July 1996.

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