K. L. Bourantas

Administration of high doses of recombinant human erythropoietin to patients with β-thalassemia intermedia : a preliminary trial

Abstract:  Four patients (1 male, 3 female, age range 16–56 yr) with β‐thalassemia intermedia were given high doses of recombinant human erythropoietin (rHuEpo), iron sulfate and folic acid in an attempt to improve their anemia. The dose schedule was: rHuEpo, 500 U/kg 3 times weekly, iron sulfate, 300 mg/d and folic acid, 5 mg/d. All patients were red blood cell transfusion‐dependent. Hematological data and fetal hemoglobin (HbF) were assayed every 2 wk. XmnI polymorphism and β‐thalassemia mutations were identified by PCR. All patients showed a moderate to high increase in hemoglobin values (mean value: 2.5 g/dl) and in 1 patient HbF levels also increased; 3 patients became red blood cell transfusion‐independent and 1 patient was able to extend the intervals between transfusions significantly. No side effects were observed during rHuEpo therapy.

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 (≤1–2 units per month), and significantly lower endogenous serum erythropoietin (EPO) and β2-microglobulin (β2-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 β2-M serum levels and slight to moderate splenomegaly.

Administration of a modified chemotherapeutic regimen containing vincristine, liposomal doxorubicin and dexamethasone to multiple myeloma patients: preliminary data.

Abstract: For elderly patients with multiple myeloma (MM), conventional melphalan and prednisone (MP) therapy has been the treatment of choice; the vincristine, doxorubicin and dexamethasone (VAD) regimen is preferred for younger patients who also receive high‐dose melphalan in combination with autologous or allogeneic bone marrow transplantation (BMT). Although survival time is similar in both the MP and VAD regimens, the continuous infusion of doxorubicin which the latter treatment entails constitutes a disadvantage along with the 4‐day hospitalization required. Doxorubicin also induces cardiotoxicity, particularly in the elderly. A modified form of VAD therapy includes liposomal doxorubicin (Caelyx®) (40 mg/kg for 1 d), oncovin (2 mg for 1 d) and dexamethasone 40 mg for 4 d per os. Doxorubicin encapsulated with liposomes has less cardiotoxicity, is more efficient and has fewer side effects than conventional doxorubicin, and it can be administered on an outpatient basis: dexamethasone can be given orally and vincristine in bolus infusion. In order to estimate its efficacy and tolerability, we administered this regimen to 12 patients (first‐line treatment in 6 patients, salvage therapy in 6 patients). All patients exhibited good tolerance to liposomal doxorubicin with no severe side effects. Eight patients achieved complete hematological remission and three partial response. One patient died before completing the treatment.

Rituximab (Anti-CD20 Monoclonal Antibody) Administration in a Young Patient with Resistant B-Prolymphocytic Leukemia

Following the administration of the human anti-CD20 monoclonal antibody IDEC-C2B8 (rituximab), a 31-year-old woman with B-prolymphocytic leukemia, who had been resistant to CHOP, fludarabine, pentostatin and 2-CdA, achieved complete remission. Rituximab was administered intravenously once a week for 4 weeks. The patient only had mild but tolerable side effects during the first cycle of therapy. She remains in complete remission 8 months following the discontinuation of treatment.

Increased prevalence of GSTM(1) null genotype in patients with myelodysplastic syndrome: a case-control study.

Background and Objective: Myelodysplastic syndromes (MDS) are clonal disorders of bone marrow stem cells characterized by ineffective hematopoiesis leading to blood cytopenia; they often progress to acute myeloid leukemia (AML). The glutathione S-transferases (GST) detoxify various agents, including those implicated in MDS. Both GSTM1 and GSTT1 genes have ‘null’ alleles and are polymorphic. We studied the impact of GTM1 and GSTT1 null genotypes on the MDS susceptibility, disease severity and laboratory indices with prognostic value for the syndrome. Material and Methods: In a hospital-based case-control study we analyzed lymphocyte DNA samples from 54 patients with MDS and 60 cancer-free controls matched for age, sex, smoking habits and origin. A multiplex polymerase chain reaction was used to genotype both GSTM1 and GSTT1 simultaneously. The χ2 test was used for statistical evaluation of the data and the odds ratios and attributable risk and population attributable risk were also calculated. Results: A significantly increased frequency of GSTM1 null genotype was found among MDS patients (57.4%) compared to controls (33.3%) (p < 0.01), while the frequency of GSTT1 null genotype was not significantly higher in MDS patients (11.1% vs. 6.66%). Neither GSTM1 and GSTT1 null genotype was associated with a particular category of the French-American-British (FAB) classification in the patients studied. Additionally, GSTM1 null genotype was associated with a significant decrease in the absolute number of neutrophils among the MDS patients. Conclusions: Individuals with GSTM1 null genotype may have increased susceptibility to MDS. Null genotypes do not seem to have be associated with FAB classification while they may be associated with putative prognostic factors.

Distribution and frequency of β‐thalassemia mutations in northwestern and central Greece

Objectives : β‐Thalassemia is a common autosomal recessive disorder resulting from over 200 different mutations of the β‐globin genes. The spectrum of β‐thalassemia mutations in Greece has been previously described in the population of the capital city of Athens, or in β‐thalassemia patients having transfusion therapy. The aim of the present study was to identify the distribution of the most common β‐thalassemia mutations in the population of northwestern and central Greece.

Treatment of 34 patients with myelodysplastic syndromes with 13-CIS retinoic acid.

Abstract:  Thirty‐four patients with myelodysplastic syndromes, 23 men and 11 women, aged between 47 and 80 years, with all types of myelodysplastic syndromes were treated with 13‐cis‐retinoic acid. The dose of retinoic acid ranged between 10 and 60 mg/m2/daily and was administered in combination with vitamin E to diminish side effects. The duration of treatment was 3 months to 5 years. Partial remission was achieved in 4 patients, 1 with RA type, 2 with RAEB and 1 with CMML. Survival ranged from 1 to 5 years. Patients who received retinoic acid developed mild side effects. In conclusion, the administration of 13‐cis‐retinoic acid improves the hematological picture in a small number of MDS patients (11.7%).

Comparison of vincristine, carmustine, melphalan, cyclophosphamide, prednisone (VBMCP) and interferon-α with melphalan and prednisone (MP) and interferon-α (IFN-α) in patients with good-prognosis multiple myeloma: a prospective randomized study

Abstract: Objectives: The purpose of the study was to evaluate, in a selected group of myeloma patients with favorable prognosis, the effect, on response and survival, of polychymotherapy compared with melphalan–prednisone, plus interferon in both arms. Methods: Eighty‐nine previously untreated patients with multiple myeloma and prognostic factors indicating a good prognosis were randomized to either oral melphalan plus prednisone (MP) in combination with recombinant interferon‐α (rIFN‐α) or combination chemotherapy with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with rIFN‐α. The two treatment groups were comparable in terms of pretreatment characteristics. Results: The overall response rate was 67.4% (2.3% complete remission, 65.1% partial response) in the MP/IFN‐α group and 69.1% (14.3% complete remission, 54.8% partial response) in the VBMCP/IFN‐α group (p=0.59). There were no differences also in response duration and overall survival between the two treatment groups. The median response duration was 39.1 months in the MP/IFN‐α group and was not reached in the VBMCP/IFN‐α group (p=0.6). Overall survival was long in both treatment groups. The estimated 5‐yr survival was 66% and 62% in the MP/IFN‐α and VBMCP/IFN‐α group, respectively (p=0.8). Toxicity was modest and treatments were well tolerated. Neutropenia (WHO grade 3 or 4) was higher, but not statistically significant, in the VBMCP/IFN‐α group. Conclusions: The results of the study show that in myeloma patients with good prognosis, combination chemotherapy alternating with interferon‐α has no advantage over conventional MP plus interferon‐α, in regard to response rate, response duration, and overall survival of patients.

Preliminary results with administration of recombinant human erythropoietin in sickle cell/β-thalassemia patients during pregnancy

To the Editor: Compound heterozygotes of sickle cell mutation and P-thalassemia syndromes are commonly found in Greece and specific areas throughout the world. Previous studies have demonstrated that pregnancy in women with this condition is associated with increased maternal morbidity, including worsening of the anemia and frequent pain crises (1). Moreover, an increased rate of spontaneous abortions, intrauterine deaths, prematurity and growth retardation complicate these pregnancies ( 1-3). Therefore, blood transfusions have been used widely either as prophylaxis or for treating the symptoms of the disease (4-7). However, although the use of prophylactic blood transfusions may be beneficial for many of these patients, there are serious concerns about the hazards of transmitting viral infections or inducing alloimmunization. Several recent studies have shown that the administration of erythropoietin in the nonpregnant state improves the symptoms and the hematological indices significantly in patients with sickle cell/pthalassemia. This is probably the result of the augmentation of the fetal hemoglobin production, which reduces the concentration of HbS and inhibits its polymerization (8, 9). In this study we report on our preliminary results with the use of recombinant human erythropoietin in 5 patients (between 18 and 40 y) with sickle cell P-thalassemia during pregnancy. As controls we have used the data of previous pregnancies in the same women. Three had one or more abortions. All had the symptoms and signs of sickle cell disease as well as long-standing pain, hemolytic episodes every 2 to 4 y r and infections. During previous pregnancies they received regular blood transfusions but also had pain crisis at the time of delivery. The patients were hospitalized for 4 wk before delivery and 1 wk after for the prevention of crises and side effects of the treatment. rHuEpo 200 U/kg/d and iron sulfate 300 mg/d were administered after approval by the scientific board of our hospital, from the 30th wk of gestation until the 4th wk after delivery. Informed consent of the patients was given and hematological tests were performed including HbF and F-cell determination, as well as measurement of the red cell indices. Hepatic and renal functions were also assessed on blood samples obtained regularly every week. Measurements of hematological parameters as: mean corpuscular hemoglobin (MCH ), mean corpuscular volume ( MCV ) and median corpuscular hemoglobin concentration (MCHC), were obtained with a Coulter Cell Analyzer. HbF was quantitated by alkali denaturation and electrophoresed within 24-48 h after blood collection. Blood sampling was done every 2nd wk over a period of 14 wk. The levels of serum erythropoietin, before treatment with rHEpo as well as during therapy, were also measured. F-cell estimation was carried out according to the Kleihauer-Betke staining method. The Xmnl status at the 158Gy of the gene which is known to stimulate the HbF synthesis was investigated by polymerase chain reaction (PCR) and subsequent digestion and electrophoresis of the PCR products in 3% agarose gel (10). The globin gene mutation in the patients and their genetic condition were identified by PCR, hemoglobin electrophoresis and microchromatography, as described previously (8). All pregnant women tolerated the administrated rHuEpo doses and only 1 had a mild vaso-occlusive crisis during therapy. The moderate increase in hemoglobin F as well as in total hemoglobin levels over the time of therapy with rHuEpo inhibited vaso-occlusion. Blood pressure, renal and hepatic functions in the 5 patients were within the normal range. All patients improved their general clinical condition and reduced significantly the requirements

Treatment of Resistant/Relapsing Chronic Lymphocytic Leukemia with a Combination Regimen Containing Deoxycoformycin and Rituximab

Background: Patients with chronic lymphocytic leukemia (CLL) are sometimes resistant to treatment or relapse soon after the administration of the currently available frontline therapy including chlorambucil-prednisolone CHOP and fludarabine. We report the beneficial effect of an alternative chemotherapeutic regimen containing 2’-deoxycoformycin (pentostatin) and the monoclonal antibody anti-CD20 (rituximab) in 5 patients with resistant/relapsing CLL. Patients: Five patients (4 men and 1 woman) with CLL at stage C, according to Binet’s classification, were included in the therapeutic protocol. The median age of the patients was 76 years (range 57–84 years). Previous treatment consisted of chlorambucil-prednisolone, fludarabine, and CHOP. The current regimen comprised six 2-week cycles of pentostatin, 4 mg/m2 i.v., combined with four cycles of rituximab, in a dose of 375 mg/m2, every other week. Results: Three patients responded to therapy, 2 achieved complete remission and 1 a partial response. Two patients did not respond to treatment. Toxicity was mild and well tolerated. The median survival duration of the responders was 19 months. These promising results suggest that salvage therapy with a combination regimen including pentostatin and rituximab may have a beneficial effect in patients with resistant/relapsing CLL.