Recombinant human erythropoietin for the treatment of anaemia in patients with chronic idiopathic myelofibrosis.

BACKGROUND: Patients with chronic idiopathic myelofibrosis (CIMF) usually present with anaemia. Treatment is often palliative and the majority of patients receive regular red blood cell (RBC) transfusions. Although recombinant human erythropoietin (rhu-EPO) has been proved effective for the treatment of anaemia in several chronic diseases, including haematological malignancies, its role in the treatment of the anaemia in CIMF is not well established. We report the beneficial effect of rhu-EPO administration in 20 patients with CIMF and discuss the parameters predicting favourable response. PATIENTS: Twenty patients with CIMF (9 women and 11 men) regularly treated with supportive RBC transfusions were included in the study. The median age was 70 years (range 45-81 years). Rhu-EPO, 10,000 U, was given subcutaneously 3 times a week. The median duration of therapy was 83 months, ranging from 13 to 87 months. RESULTS: Treatment was considered effective if haemoglobin levels increased over 2 g/dl within 12 weeks after enrolment or the RBC transfusion requirements were reduced by 50% within the same interval. Twelve patients (60%) responded to therapy. Responders were mainly female, had smaller spleen size (p = 0.024), low RBC transfusion requirements (< or = 1-2 units per month), and significantly lower endogenous serum erythropoietin (EPO) and beta2-microglobulin (beta2-M) levels when compared with non-responders (p < 0.0001 and 0.00001, respectively). Treatment was well tolerated and none of the patients was withdrawn from the treatment protocol because of side effects. CONCLUSIONS: Rhu-EPO administration is an effective, safe and well-tolerated treatment for patients with CIMF and anaemia leading to a significant reduction in RBC transfusion requirements. Factors predicting favourable response are low endogenous EPO and beta2-M serum levels and slight to moderate splenomegaly.

Beneficial effect of rituximab in combination with oral cyclophosphamide in primary chronic cold agglutinin disease.

Cold agglutinin disease (CAD) is an uncommon autoimmune hemolytic anemia characterized by B-cell proliferation. Conventional therapies for primary CAD such as corticosteroids, oral alkylating agents, splenectomy, interferon alpha, and plasma exchange are often ineffective at controlling the disease. The anti-CD20 monoclonal antibody rituximab (MabThera) depletes B-lymphocytes and thereby interferes with the production of cold agglutinin. We describe an elderly patient with primary (idiopathic) chronic CAD refractory to steroids who was successfully treated with 4 weekly infusions (375 mg/m2) of rituximab and 6 months of oral cyclophosphamide at a dosage of 60 mg/m2 per day. The increase in hemoglobin level and the decline in the plasma cold agglutinin titer were rapid (from the second rituximab infusion). The hematologic remission persisted for at least 8 months after treatment start, with no adverse effects. Rituximab and cyclophosphamide may be supplementary therapeutic modalities whose combination warrants further clinical investigation.

T-cell receptor gammadelta-large granular lymphocytic leukemia associated with an aberrant phenotype and TCR-Vbeta20 clonality.

Large granular lymphocytic (LGL) leukemia is a rare heterogenous disorder of mature lymphocytes with a characteristic morphology, multiple autoimmune disorders and indolent clinical course. Most cases exhibit a T-cell phenotype of CD3, CD8 and CD57 positivity, while the minority exhibit a CD2, CD56, and CD16 positive NK-cell phenotype. We report a case of a 71-year-old female suffering from a TCRgammadelta positive T-cell leukemia with a morphology compatible to LGL leukemia. She referred to the hospital for investigation of mild anemia, lymphocytosis, neutropenia and hyperglobulinemia. Peripheral blood and bone marrow were occupied by mature large granular lymphocytes with abundant azurophilic granules. The immunophenotype was CD3+, CD2+, CD5+, CD7+, CD4-, CD8-, CD16-, CD56-, CD57- and the Vbeta repertoire analysis showed clonal reactivity with Vbeta20 mAb. The patient was diagnosed as having T-LGL and was treated with G-CSF. So far, she experiences an indolent clinical course. To our knowledge, this is a rare case of TCRgammadelta positive T-LGL leukemia with the aberrant immunophenotype of CD3+, CD4-, CD8-, CD16-, CD56-, CD57-.

Rheumatoid arthritis and B-cell chronic lymphocytic leukemia.

The association between lymphoproliferate malignancies, especially lymphoma, and rheumatoid arthritis (RA) has been confirmed by several studies. However; there are few reports of RA patients who developed B-cell chronic lymphocytic leukemia (B-CLL) and vice versa. We report a patient with B-CLL who developed RA and another with RA who presented with B-CLL during follow-up. We discuss the incidence of B-CLL among the RA population and the possible interaction of the pathogenetic mechanisms of these two entities.

Renal abnormalities in patients with sickle cell-beta thalassemia.

We examined renal abnormalities in Greek patients with sickle-cell beta thalassemia (S-beta thal). A total of 17 patients aged 16-59 years suffering from S-beta thal and 17 age- and sex-matched healthy controls were studied. In all individuals we carried out a detailed study of renal function including electrolytes in serum and urine, concentrating or diluting ability, urine acidification ability, glomerular filtration rate (GFR), and hormones [such as plasma renin activity (PRA), serum aldosterone, and erythropoietin (EPO)]. Though the GFR did not differ significantly in patients and controls, half the patients had either supranormal or subnormal values. Serum potassium and uric acid were significantly higher in patients than controls. Serum phosphorus was similar in both groups, though patients with S-beta thal had significantly lower phosphate excretion indices. All patients were unable to maximally concentrate the urine, and seven also had limited ability to maximally dilute it. Five patients had incomplete distal renal tubular acidosis. Four had mild proteinuria, and six had microalbuminuria. Serum EPO and aldosterone were higher in S-beta thal patients than controls, but there was no difference in PRA between the two groups. There was a strong correlation between hemoglobin concentration and EPO levels, which was strongest in patients with GFR < 50 ml/min. We conclude that patients with S-beta thal, like sickle-cell anemia patients, present multiple abnormalities of renal function.

Solitary bone plasmacytoma in a young patient.

Plasma cell disorder, a disease of the elderly, is extremely rare in those below 30 years of age. A young 18 year old patient with solitary plasmacytoma is described in this case report.

Two siblings with chronic myelogenous leukemia.

In the present study we report the occurrence of Chronic Myelogenous Leukemia in two siblings (brother and sister) 47 and 62 years old respectively. These two cases raised the question of a possible genetic prodiathesis or a possible trasmission (environmental factor) cause.

Treatment of MDS patients with recombinant human erythropoietin and the role of GSTs.

Glutathione S-transferases (GSTs) are a group of enzymes involved in the detoxification process of carcinogens and other substances. The genes encoding isoenzymes M1 and T1 have "null" alleles, which are polymorphic in humans. Our purpose was to examine whether the GSTM1 and GSTT1 homozygous null genotypes have an impact on the response to recombinant human erythropoietin (rhuEpo) treatment in MDS patients. We analyzed lymphocyte DNA samples from 27 patients with all types of myelodysplastic syndromes (MDS) at the time of diagnosis. All patients were scheduled to receive rHuEpo in doses of 150 u/Kg/day for a period of 12 weeks in order to obtain and maintain stable responses. A multiplex polymerase chain reaction (PCR) was used to genotype both GSTM1 and GSTT1 simultaneously, in responders and non-responders to rhuEpo with respect to various pretreatment parameters: haemoglobin, white blood cell count, platelets, serum erythropoietin, transfusion requirements and bone marrow blasts. The data obtained were evaluated by chi2 test and odds ratio were extracted. Twelve out of 27 evaluated patients demonstrated an erythroid response (44%). Nine out of the 12 patients (75%) responding after 12 weeks of treatment had GSTM1 null genotype (OR=3.4). In contrast, only 1 responder (8.3%) was homozygotes of GSTT1 null genotype. Furthermore, no statistically significant difference in the response rate of the different MDS subgroups was observed. Our results suggest that a treatment with rHuEpo may be effective in achieving a stable erythroid response in MDS patients who carry an homozygous deletion of the GSTM1 gene.

Lack of HLA-DR expression in a patient with B-chronic lymphocytic leukemia.

We describe a rare case of a patient with chronic lymphocytic leukemia (CLL) whose immunophenotype analysis revealed lack of HLA-DR in B-cells.

Successful treatment of refractory anemia with a combination regimen containing recombinant human erythropoietin, low-dose methylprednisolone and nandrolone.

Myelodysplastic syndromes (MDS) are a heterogenous group of hematological clonal malignancies. Patients belonging to the refractory anemia (RA) subtype are usually treated with recombinant human erythropoietin (EPO). Not all patients respond to EPO administration and they are strictly dependent on supportive therapy with red cell blood (RBC) transfusions. The aim of this study was to investigate the efficacy of an alternative combination regimen containing EPO, low-dose methylprednisolone and nandrolone decanoate, in patients with RA unresponsive to EPO administration alone. Ten patients, 4 women and 6 men, median age: 70 years (range: 55-78 years) with refractory anemia unresponsive to EPO administration and RBC transfusion-dependent were included in the study. Median hematological data at baseline were Hb: 8.7 g/dl, (range 6.2-9.8), WBC: 3.35x10(9)/l (range 2.1-4), PLT: 82.5x10(9)/l (range 59-110). EPO 150 U/Kg three times/week subcutaneously, low-dose methylprednisolone 8 mg/day orally and nandrolone decanoate (Decadurabolin) 50 mg two-times/week intramuscularly were administered. As complete response (CR) to treatment was considered the normalization of the peripheral blood and bone marrow smears and biopsy. As partial response (PR) was considered increase in Hb level > or = 2 g/dl, or up to 10 g/dl and discontinuation of RBC transfusions. The response to therapy was evaluated on the 4th week after the initiation of the combination treatment. Bone marrow smear evaluation was carried out at baseline and every six months afterwards. After a 4-week treatment all patients achieved PR and discontinued RBC transfusions. Median and range hematological values on the 4th week after treatment initiation were Hb: 11.2 g/dl, (range: 9.8-12.8), WBC: 4.4x10(9)/l (3.5-6.6), PLT: 130x10(9)/l (95-160). The increase observed in hematological values was significant (p = 0.0001, 0.0004 and < 0.0001, respectively, for Hb, WBC and PLT counts). Treatment was well tolerated. Furthermore, two women, on treatment with the combination regimen, achieved CR one after six months and the second after 12 months. They are alive after 5 years from initiation of the combination treatment. After a median period of 18 months (range 12 to 20 months) in PR three men developed acute leukemia; they received intensive antileukemic chemotherapy without any response and died during the phase of pancytopenia. Three other men achieved CR, one after 6 and two after 12 months of therapy and they are on regular follow-up. Two women after 10 and 14 months in PR developed acute leukemia and died. In conclusion, combination therapy with EPO, nandrolone decanoate and low-dose methylprednisolone may be effective as an alternative treatment for RBC transfusion-dependent patients with RA unresponsive to EPO administration alone.

A single-center, retrospective study of management and outcome of 45 elderly AML patients, diagnosed in 2001.

Acute myeloid leukemia (AML) predominantly affects older adults, a population with a poor prognosis, due to age, comorbidities and forms of disease. We present a retrospective study of 45 patients older than 60 years of age, with AML, who were diagnosed and/or treated in our clinic in the year 2001. Our study refers to 32 men, 63-80 years of age and 13 women, 62-85 years of age. Fourteen of them were diagnosed as de novo leukemia while 31 developed secondary leukemia, due to myelodysplasia, chronic myeloid leukemia and essential thrombocytemia. A therapeutic protocol that included 2 courses of induction chemotherapy with idarubicin 8mg/m2 for 3 days, aracytin 100 mg/m2 for 5 days and etoposide 75 mg/m2 for 5 days, followed by 2 courses of consolidation chemotherapy with aracytin 800 mg/m2/d for 4 days, was administered. In patients with acute promyelocytic leukemia we additionally administered all trans retinoic acid. Those with erythroleukemia also received erythropoietin, 10,000 IU 3 times a week. All patients received supportive therapy with blood products and G-CSF during blood marrow aplasia. Four patients refused therapy and three patients received only blood product support because of poor performance status. Nine out of the 38 patients who received chemotherapy (23.7%) achieved a complete remission after treatment, while, 13 out of 38 (34.2%) only a partial one (overall remission rate: 57.9 %). Ten patients relapsed in <6 months and 12 patients relapsed in >6 months. Patients who received only supportive treatment died 2-5 months after initial diagnosis. During therapy, 16 patients (42.1%) died due to: infection, cerebrovascular or gastrointestinal bleeding and acute myocardial infarction. In conclusion, it appears that a high percentage of the elderly patients with AML, despite the unfavourable prognosis, responded to chemotherapy (57.9%) and achieved longer survival durations compared to patients who refused therapy or received supportive treatment alone. Unfortunately, a large number of them exhibited serious complications during treatment, with a mortal outcome. Close follow-up and supportive care highly contributed to an improvement of treatment outcome in elderly patients with acute myeloid leukemia.

Skin lesion's treatment with alfa interferon in a patient with B-CLL.

Treatment with recombinant alfa-2b-interferon in a patient with advanced B-CLL resulting in complete remission of skin lesions after one month therapy is reported in this paper. Interferon was administered subcutaneously three times weekly. Six months later while the treatment continued, the disease remained stable.

Interleukins, TNF-alpha and beta-2M in patients with B cell chronic lymphocytic leukemia.

In order to investigate the possible existence of a prognostic factor for B cell chronic lymphocytic leukemia (B-CLL), we determined the serum levels of TNF-alpha, IL-1a, IL-1b, IL-2, sIL-2R, IL-6, IL-10 and beta-2M in 20 patients. We observed significant changes in sIL-2R and beta-2M levels, whereas in all stages of disease, TNF-alpha and other interleukins exhibited only mild changes. An excellent correlation between sIL-2R and beta-2M levels and disease activity wes reported. Patients with aggressive disease (Rai stages III and IV and Richter's syndrome) had increased levels. Patients who responded to therapy and with improved clinical status had decreased sIL-2R and beta-2M levels. However, patients with progressive disease and no response to therapy were associated with increased levels of sIL-2R and beta-2M. In conclusions, as serum levels of sIL-2R and beta-2M are increased in the aggressive stages of B-CLL, they may be used as reliable markers for monitoring B-CLL activity, showing response to treatment and early relapse and/or disease progression.

Patients with multiple myeloma and solid tumors: six case reports.

Six patients with multiple myeloma (MM) and a second non-hematological neoplasm (solid tumor) are documented in this study. Two patients had a previous history of adenocarcinoma of the colon prior to MM diagnosis; in three patients a second neoplasm (lung cancer, adenocarcinoma of the urinary bladder and adenocarcinoma of the colon) appeared at the time of MM diagnosis; one patient, a woman with a six-year history of MM, developed hepatoma. The two patients who had had a neoplasm of the colon ten years before and the patient with bladder carcinoma, responded to MM therapy. The patient with lung cancer and the patient with adenocarcinoma of the colon died; the last patient, with MM and liver cancer, is alive but with aggressive disease. In conclusion we have found that in MM patients a second neoplasm may develop or co-exist, in greater frequency than that of the general population.

Chronic myelogenous leukemia terminating in acute megakaryoblastic leukemia. Case report.

A case of chronic myelogenous leukemia (CML) terminating in acute megakaryoblastic leukemia (AMKL) is here presented. Megakaryoblasts were identified by the presence of platelet peroxidase in the bone marrow as well as in pleural effusion and ascites. The clinical course, morphology and immunologic studies of the blast cells are described in this report.

Coexistence of myelodysplastic syndrome and multiple myeloma.

We describe the simultaneous presentation of myelodysplastic syndrome (MDS) and multiple myeloma (MM). Our patient had MDS (RAEB type) and bone marrow infiltration (40% plasma cells), as well as biclonal paraprotein. Patients with MM, MDS have been reported after chemotherapy but few cases documenting the coexistence of MDS and MM at diagnosis have been reported in the literature.

Skin and gingival lesions in a young woman with B-prolymphocytic leukemia (B-PLL).

B-PLL has not been often associated with diffuse skin involvement or oral lesions. We present a 32 year-old woman in whom skin and gingival manifestations were the prominent clinical signs of disease relapse.

Preliminary results of amifostine administration in combination with recombinant human erythropoietin in patients with myelodysplastic syndromes.

Amifostine is a cytoprotective agent mainly used in cancer therapies, in order to ameliorate the toxic effects of anticancer chemotherapy and radiotherapy. In the past years an intriguing number of applications of amifostine have been identified; one of these is bone marrow cells protection and stimulation. Amifostine was administered in seven patients with myelodysplastic syndromes, four males and 3 females aged between 67 and 78 years old, in order to estimate its efficacy in reducing the need for red blood cells transfusions. Two patients had RAEB, four RA and one RARS. The drug was administered in an outpatient basis in a dose of 300 mgr/m2, three times weekly for at least four weeks. We administered at the same time erythropoietin 10.000 U subcutaneously. All patients received daily supplementation of oral ferrum sulfate and folic acid. Three patients, a woman with RA and two men, one with RA and another with RAEB improved the levels of Hb beyond 12,0 gr/dl and did not receive blood transfusions after the second week of treatment. The drug was well tollerated without any side effects in all of the patients.

Recombinant human erythropoietin treatment of postpartum anemia. Preliminary results.

OBJECTIVES: The aim of this study was to investigate the efficacy of recombinant human erythropoietin (rHuEpo) in postpartum anemia. STUDY DESIGN: At the University Hospital of Ioannina, rHuEpo was administrated subcutaneously to twenty anemic women (hemoglobin [Hb]<10 g/dl), for 15 days following delivery; all were given iron and folic acid per os. Twenty other women (the control group) with postpartum anemia (Hb<10 g/dl), received only iron and folic acid. The Mann-Whitney U-test was used for the comparison of hematological indices between the two groups, on days 1, 3, 5, 10, 15 and 40 postdelivery. RESULTS: On day 3, reticulocyte counts were significantly higher in the women who received rHuEpo, as compared to the controls (P<0.05). The mean Hb value increased to >2 g/dl in the group undergoing rHuEpo therapy as compared to 0.7 g/dl in the control group on day 5 (P<0.05). Furthermore, two women in the control group required blood transfusions, while no transfusions were required by the rHuEpo group. CONCLUSIONS: rHuEpo administration is useful for a more rapid amelioration of hematological indices in women with postpartum anemia. Further, the dose given in this study was not associated with significant side-effects.