Successful combined therapy with ATG, cyclosporin and G-CSF for both liver dysfunction and bone marrow failure in hepatitis-associated aplastic anemia]

A 28-year-old man developed cryptogenic hepatitis in January 1999, and treatment with glycyrrhizic acid improved his liver function. From June, however, pancytopenia began to develop gradually. The patient received G-CSF against leukocytopenia (WBC 1,100/microliter, neutrophils 590/microliter) and was transferred to our hospital in August 1999. A diagnosis of hepatitis-associated aplastic anemia was made on the basis of liver dysfunction (AST 156 IU/l, ALT 386 IU/l), hypoplastic bone marrow, and pancytopenia (WBC 4,400/microliter, neutrophils 3,340/microliter under G-CSF administration, Hb 9.8 g/dl, platelets 2.4 x 10(4)/microliter, reticulocytes 4.7 x 10(4)/microliter). Immediately after starting combined therapy with ATG, cyclosporin, and G-CSF, his liver function began to improve and was normalized on day 7. Pancytopenia began to ameliorate on day 9, and blood parameters on day 60 were WBC 4,200/microliter (without G-CSF administration), Hb 12.0 g/dl, platelets 9.0 x 10(4)/microliter, and reticulocytes 4.1 x 10(4)/microliter. Although the prognosis of hepatitis-associated aplastic anemia is generally poor, immunosuppressive therapy was markedly effective for both pancytopenia and hepatic dysfunction in the present case.     

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.     

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.     

Very low doses of GM-CSF administered alone or with erythropoietin in aplastic anemia.

PURPOSE AND RATIONALE: There has been no previously published experience with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses less than 15 micrograms/m2/d in patients with aplastic anemia, and most observations have been made at doses of 100 to 500 micrograms/m2/d (2.5 to 12.5 micrograms/kg/d). The benefits of using considerably lower doses, if effective, should include a decrease in cost and in side effects. We have therefore used very low doses of GM-CSF to treat a group of patients with aplastic anemia. Additionally, since severe anemia is often a problem in these patients, we recently started administering erythropoietin along with the GM-CSF. Herein we report the results of very-low-dose GM-CSF therapy in patients with aplastic anemia and our preliminary findings in those individuals who received combination therapy. PATIENTS AND METHODS: We administered recombinant human GM-CSF subcutaneously at doses of 5 to 20 micrograms/m2/d ("very-low-dose GM-CSF") to 12 patients with aplastic anemia. In addition, a 13th patient received erythropoietin together with the GM-CSF regimen, and three of the 12 individuals who initially received 1 or more months of GM-CSF alone were later also given erythropoietin (4,000 U/d subcutaneously). RESULTS: In five of 12 patients (42%) treated with very-low-dose GM-CSF, an increase in neutrophil counts (2.0- to 6.7-fold) was noted, and one of these subjects attained a bilineage response (neutrophil counts, 0.3 to 1.75 x 10(9)/L; platelet counts, 8 to 169 x 10(9)/L). Moreover, a sixth patient showed a rise in platelet counts (19 to 80 x 10(9)/L) without a concomitant increase in neutrophils. Constitutional side effects were minimal. Combining erythropoietin and very-low-dose GM-CSF produced a bilineage response (neutrophils, 1.0 to 3.0 x 10(9)/L; hemoglobin, 7.4 to 9.4 g/dL) in the one patient who received erythropoietin together with the GM-CSF from the time that GM-CSF was initiated. In one of the other patients who were given combination therapy, the addition of erythropoietin appeared to enhance the response; this patient demonstrated a neutrophil response to GM-CSF alone and a trilineage response (neutrophils, 0.8 to 3.75 x 10(9)/L; hemoglobin, 7.0 to 13.1 g/dL; and platelets, 10 to 34 x 10(9)/L) to the combination. No toxicity was associated with the addition of erythropoietin. CONCLUSIONS: Our observations suggest that (1) very low doses of GM-CSF (5 to 20 micrograms/m2/d subcutaneously) may be used initially in neutropenic patients with aplastic anemia, and the dose subsequently increased only in patients who do not respond; and (2) the administration of erythropoietin together with GM-CSF is well tolerated, can augment responsiveness in some patients, and deserves further study.     

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.     

Administration of low-dose interleukin-2 plus G-CSF/EPO early after autologous PBSC transplantation: effects on immune recovery and NK activity in a prospective study in women with breast and ovarian cancer

This study evaluated the effects of low-dose IL-2 plus G-CSF/EPO on post-PBSC transplantation (PBSCT) immune-hematopoietic reconstitution and NK activity in patients with breast (BrCa) and ovarian cancer (OvCa). To this end, two consecutive series of patients were prospectively assigned to distinct post-PBSCT cytokine regimens (from day +1 to day +12) which consisted of G-CSF (5 microg/kg/day) plus EPO (150 IU/kg/every other day) in 17 patients (13 BrCa and 4 OvCa) or G-CSF/EPO plus IL-2 (2 x 10(5) IU/m(2)/day) in 15 patients (10 BrCa and 5 OvCa). Hematopoietic recovery and post-transplantation clinical courses were comparable in G-CSF/EPO- and in G-CSF/EPO plus IL-2-treated patients, without significant side-effects attributable to IL-2 administration. In the early and late post-transplant period a significantly higher PMN count was observed in G-CSF/EPO plus IL-2-treated patients (P = 0.034 and P = 0.040 on day +20 and +100, respectively). No significant differences were found between the two groups of patients in the kinetics of most lymphocyte subsets except naive CD45RA(+) T cells which had a delayed recovery in G-CSF/EPO plus IL-2 patients (P = 0.021 on day +100). No significant difference was observed between NK activity in the two different groups, albeit a significantly higher NK count was observed in G-CSF/EPO plus IL-2 series on day +20 (P = 0.020). These results demonstrate that low-dose IL-2 can be safely administered in combination with G-CSF/EPO early after PBSCT and that it exerts favorable effects on post-PBSCT myeloid reconstitution, but not on immune recovery.     

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.     

Transformation of severe aplastic anemia into acute myeloblastic leukemia with monosomy 7

 A cytogenetically normal man with severe aplastic anemia was treated with granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), cyclosporin A, anti-thymocyte globulin, and interleukin-6 (IL-6), which resulted in a gradual improvement in his neutrophil count and hemoglobin level. After 2 years of the therapy, monosomy 7 was detected during cytogenetic analysis of his bone marrow, which evolved during a period of 5 months into acute myeloblastic leukemia. An in vitro proliferation assay of cytokine responses showed that leukemic blasts were sensitive only to G-CSF, and not to EPO or IL-6. Although allogeneic bone marrow transplantation from an HLA-matched unrelated donor was carried out in the non-remission stage, the patient died of systemic fungal infection on day 25, without any evidence of hematological engraftment. As long-term use of cytokines and immunomosuppressants in patients with severe aplastic anemia may induce or hasten the onset of a malignant transformation, careful attention must be paid to clonal evolution. Due to the poor prognosis of secondary myelodysplasia and leukemia, allogeneic bone marrow transplantation for such patients must be carried out early in the course of the disease. Received: 27 September 1995 / Accepted: 19 December 1995     

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.     

Autologous transplantation of Ph-negative peripheral blood stem cells for treatment of chronic myelogenous leukemia

A 21-year-old man, diagnosed in March 1997 as having chronic myelogenous leukemia (CML), received hydroxyurea followed by daily interferon (IFN) until December 1998, when the additional chromosome abnormality of +8 appeared. As no suitable matched donor was available, the patient received mobilization therapy consisting of mini-ICE (idarubicin, cytarabine, etoposide) followed by G-CSF subcutaneously. During hematopoietic recovery, a total of 12 x 10(6)/kg CD34-positive cells were harvested. Cytogenetic analysis of peripheral blood stem cell (PBSC) products using FISH revealed 1% BCR/ABL fusion signals. In March 1999, he received conditioning therapy consisting of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by infusion of 5 x 10(6)/kg CD34-positive cells. A neutrophil count of 500/microliter and a platelet count of 5 x 10(4)/microliter were attained by days 20 and 38, respectively. Bone marrow aspirates showed 2.6% BCR/ABL fusion signals on day 35 after autologous PBSC transplantation, and the patient remained in chronic phase until the sixth month, when a cytogenetic relapse (Ph, +8:4/20) occurred. These observations suggest that Ph-negative progenitor cells can be harvested using a mini-ICE regimen followed by G-CSF, and that autologous PBSC transplantation is feasible in patients with CML resistant to IFN.     

Bilineage response in refractory aplastic anemia patients following long-term administration of recombinant human granulocyte colony-stimulating factor.

5 patients with refractory aplastic anemia (AA) received long-term administration (2-11 + months) of recombinant human G-CSF (rhG-CSF) in doses from 250-500 micrograms/body/day by intravenous infusion or 75-300 micrograms/body/d by subcutaneous injection. All 5 evaluable patients showed a substantial increase in absolute neutrophil count (ANC) with a recovery of myeloid components in the bone marrow after 1 to 2 months of treatment. Interestingly, 2 out of the 5 patients showed a dramatic improvement in severe anemia after 2 to 4 months of treatment accompanying a recovery of erythroid components in the bone marrow. In addition, there was no serious infection before or during therapy. Long-term administration of rhG-CSF was well tolerated because of its minimal toxicity. Clonal assay revealed a recovery of myeloid progenitors in all patients and a recovery of erythroid progenitors in 3 out of the 5 patients. These results suggest that long-term administration of rhG-CSF at least mobilizes residual myeloid as well as erythroid progenitor cells and induces a bilineage response in severe refractory AA.     

The effect of recombinant human granulocyte colony-stimulating factor (rG-CSF) on childhood neutropenias]

The clinical effect of recombinant human granulocyte colony-stimulating factor (rG-CSF), produced by Chinese hamster ovary cells, was studied in 27 patients with childhood neutropenias. The sample consisted of 8 patients with congenital neutropenia (Kostmann type), 9 with neutropenia with miscellaneous causes (5 chronic benign, 2 associated with hypogammaglobulinemia, 1 drug-induced, and 1 hypoplastic type), 3 with cyclic neutropenia, and 7 with severe aplastic anemia. The rG-CSF was given subcutaneously (or in a few cases intravenously) at a dose of 2 micrograms/kg/day for 7 days and 5 micrograms/kg/day for additional 7 to 28 days in cases with poor response. The rG-CSF was effective in 18 of 27 cases (67%). Patients with congenital neutropenia and aplastic anemia responded less frequently and poorly. The mean level of absolute neutrophil counts of 8 congenital neutropenia cases increased from 88/microliters to 2,718/microliters. That of 9 miscellaneous cases changed from 189/microliters to 7,224/microliters at a dose of 2 micrograms/kg/day. In 7 aplastic anemia cases pretreatment level of 220/microliters rose to 851/microliters, usually after increasing the dose up to 5 micrograms/kg/day. The rG-CSF was apparently effective in 3 cases of cyclic neutropenia. In any type of neutropenia, the effect was largely transient; after the discontinuation of rG-CSF, the absolute neutrophil counts tended to decrease to pretreatment levels within 1 to 2 weeks. The G-CSF was well tolerated, and only one case with mild lumbago and another with minimal elevation of transaminases were observed. We conclude that the rG-CSF can be effective for treating various types of childhood neutropenia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Severe aplastic anemia remarkably improved by a treatment with antilymphocyte globulin, high-dose methylprednisolone and danazol

Sixteen-years-old female with severe aplastic anemia received a therapy combined with antilymphocyte globulin (ALG), high-dose methylprednisolone (m-PSL) and danazol. At the hospitalization, hematological examination demonstrated as follows; reticulocyte 21,000/microliters, granulocyte 350/microliters, platelet 10,000/microliters and hypocellular bone marrow. Treatment schedule were 1) m-PSL 1,000 mg (day 1-4), 500 mg (5-8)--then tapered. 2) ALG lg/day (day 4-8) 3) danazol 600 mg/day. During ALG administration, leukocytopenia and thrombocytopenia appeared but thereafter hematological recovery was obtained and the patient was free from supportive care. She developed mild diabetes mellitus and moderate liver dysfunction, nevertheless, both of which were controlled. At 3 months after the beginning of the treatment, hematological examination demonstrated as follows; reticulocyte 236,000/microliters, granulocyte 1,900/microliters, platelet 56,000/microliters and normocellular bone marrow. Although this immunosuppressive therapy was remarkably effective to this patient, immunological relation to the onset of aplastic anemia was not demonstrated in in vitro examination. This combined therapy seems to be effective one for patients with severe 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.     

Retardation of platelet recovery after autologous stem cell transplantation in a patient with acute lymphoblastic leukemia: possible role of decreased thrombopoietin production by bone marrow stromal cells

A 16-year-old boy was diagnosed as having acute lymphoblastic leukemia and underwent autologous stem cell transplantation at the time of his second complete remission. Retardation of platelet recovery was evident at day 90 (< 5 x 10(4)/microliter), and at day 660 after transplantation the platelet count was 8.5 x 10(4)/microliter. Neutrophils and RBCs showed only slightly retarded recovery. Bone marrow stromal cells, which are thought to play an integral role in megakaryopoiesis, were examined. Although TPO mRNA expression per cell was normal, CFU-F was significantly decreased, resulting in a decrease of total TPO mRNA expression. In contrast, expression of G-CSF mRNA per cell was increased. It was thought that chemotherapy before bone marrow transplantation may have reduced the number of stromal cells, leading to retardation of platelet recovery because of low TPO expression.     

Effect of granulocyte-colony stimulating factor on empiric therapy with flomoxef sodium and tobramycin in febrile neutropenic patients with hematological malignancies. Kan-etsu Hematological Disease and Infection Study Group

The clinical effects of concomitant use of granulocyte-colony stimulating factor (G-CSF) on empiric antibiotic therapy in febrile neutropenic patients were evaluated in a randomized fashion. Two hundred and fourteen neutropenic febrile episodes (neutrophil counts < 1.0 x 10(9)/l) were treated with flomoxef sodium and tobramycin with or without G-CSF. The resolution of fever at day 4 (excellent response) or at day 7 (good response) was deemed effective. Among 157 evaluable episodes, the observed excellent responses were 31 (38.8%) and the good responses were 20 (25.0%) in the G-CSF group; those in the control group were 26 (33.8%) and 25 (32.5%), respectively. The overall efficacy rate was 63.8% (51/80) in the G-CSF group and 66.2% (51/77) in the control group (not significant). The initial neutrophil count was 0.186 +/- 0.249 x 10(9)/l in the G-CSF group and 0.235 +/- 0.290 x 10(9)/l in the control group, and rose to 2.889 +/- 4.198 x 10(9)/l and 0.522 +/- 0.844 x 10(9)/l, respectively, at day 7. These results indicate that G-CSF does not affect the rate of response to empiric antibiotic therapy in febrile neutropenic patients, although a significant effect of G-CSF was observed on neutrophil recovery.     

Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin [see comments]

We treated myelodysplastic syndrome patients (MDS) with both recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human erythropoietin (EPO) to determine whether such combination therapy resulted in improvement of their anemias. Twenty- four of 28 patients begun on study completed the protocol and were evaluable for erythroid responses. Therapy was initiated with G-CSF at 1 micrograms/kg administered by daily subcutaneous injection and adjusted to either normalize or double the neutrophil count. EPO was then administered by daily subcutaneous injection at a dose of 100 U/kg and dose-escalated to 150 and 300 U/kg every 4 weeks while continuing the G-CSF. Changes in absolute reticulocyte count, hematocrit level, and need for RBC transfusions were compared with pretreatment values as well as other blood cell counts. Ten of 24 patients (42%) had erythroid responses, whereas all patients had neutrophil responses. Six previously transfused patients no longer required RBC transfusions during the treatment period. Erythroid responses were found to be independent of patient age, French-American-British subtype, duration of disease, prior RBC transfusion requirements, or cytogenetic abnormalities at presentation. Pretreatment serum EPO levels were lower in erythroid-responding as compared with nonresponding patients (median 157 v 600 U/L; P = .05). The combined treatment modality was generally well tolerated. We conclude that a substantial percentage of MDS patients had both erythroid and myeloid responses when treated with the combination of G-CSF and EPO.     

The increase of the rate of hemopoietic recovery and clinical benefit of the erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) with peripheral blood progenitor cells (PBPC) after intensive cyclic chemotherapy in high-risk breast cancer patients

The role of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) combination in hemopoietic recovery was studied in patients with high-risk breast carcinoma and compared to a control group of previously treated identical patients who were not given EPO plus G-CSF. Eleven consecutive patients admitted to this study had Stage III or IV breast cancer. They received 6 cycles of intensive chemotherapy (epirubicin 150 mg/m2 and cyclophosphamide 1300 mg/m2). The 1st cycle served for mobilization of peripheral blood progenitor cells (PBPC). At its end leukaphereses collections of PBPC were performed to be used as hematologic support (PBPCT) in the 5 remaining cycles. The administration of EPO plus G-CSF was started when leukocyte (WBC) count in peripheral blood dropped below 1 x 10(9)/l and hemoglobin (Hb) level fell below 100 g/l. The treatment was stopped when leukocyte count rose to 5 x 10(9)/l and Hb to 130 g/l. EPO plus G-CSF combination after PBPCT produced significant effects in terms of hemopoietic recovery, clinical benefit and supportive care requirements when compared with 12 historic control patients: Periods of leukopenia were shorter which resulted in reduced risk of infectious complications. The grades of leukopenia in the study and control groups were as follows: grade 4 (36 vs. 18%), grade 3 (57 vs. 30%), grade 2 (7 vs. 13%) respectively. Significantly shorter was the time of PLT recovery < 50 x 10(9)/l (p < 0.001). The grades of thrombocytopenia were: grade 4 (29 vs. 11%), grade 3 (21 vs. 12%), grade 2 (25 vs. 36%) respectively. The number of necessary transfusions was significantly reduced as well as the length of hospital stay (p < 0.001). In conclusion, our results obtained in this study confirm that combination of EPO plus G-CSF not only increases the rate of hemopoietic recovery, reduces the number of necessary red blood cell and platelet transfusions but, at the same time, simplifies the clinical management and is more tolerable for the patients.     

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.     

Hematopoietic growth factors as adjuncts to antiretroviral therapy.

Anemia and neutropenia are common complications of HIV infection. Antiretroviral therapy with zidovudine exacerbates bone marrow suppression by inhibiting proliferation of blood cell progenitor cells. In addition, treatment for opportunistic infections or malignancies can involve the use of myelosuppressive drugs. As a consequence, severe anemia and neutropenia can result, thereby limiting the utilization of antiretroviral drugs. Since antiretroviral therapy can increase survival, drugs that ameliorate myelosuppression are important adjuncts in the treatment of HIV-infected patients. Three hematopoietic growth factors are effective in the treatment of anemia or neutropenia. In four placebo-controlled trials, erythropoietin (EPO) at doses up to 600 U/kg/wk decreased mean transfusion requirements by 37%, increased mean hematocrit by 4.5% and corrected anemia in the majority of patients receiving zidovudine over a 12-week period. In a separate study, granulocyte colony-stimulating factor (G-CSF) corrected leukopenia and isolated neutrophil defects in 22 patients with AIDS without altering HIV expression. When erythropoietin was added to the regimen, combined G-CSF and EPO corrected both anemia and leukopenia and lessened subsequent zidovudine toxicity. Similarly, granulocyte macrophage-colony-stimulating factor (GM-CSF) corrected leukopenia and pre-existing neutrophil defects in patients with HIV infection. In controlled and uncontrolled trials, GM-CSF also appears to reduce toxicity from zidovudine, ganciclovir, and antineoplastic therapy. New combinations of hematopoietic stimulants are being used to decrease the toxicity from combination antiretroviral therapy with alpha interferon and cytotoxic chemotherapy in the treatment of AIDS-related malignancies.(ABSTRACT TRUNCATED AT 250 WORDS)