Carlo Bodenizza

Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes

Thirty‐seven anaemic subjects with low‐to‐intermediate risk myelodysplastic syndrome (MDS) received the highly glycosylated, long‐acting erythropoiesis‐stimulating molecule darbepoetin‐alpha (DPO) at the single, weekly dose of 150 μg s.c. for at least 12 weeks. Fifteen patients (40·5%) achieved an erythroid response (13 major and two minor improvements, respectively, according to International Working Group criteria). Such results are currently maintained after 7–22 months in 13 of the responders, one of whom required iron substitutive therapy during the treatment. One patient relapsed after 4 months. Another responder died after 5 months because of causes unrelated to the treatment. No relevant side‐effects were recorded. At multivariate analysis, significant predictive factors of response were baseline serum levels of endogenous erythropoietin <100 IU/l, absent or limited transfusional needs, no excess of blasts and hypoplastic bone marrow. This study suggests that DPO, at the dose and schedule used, can be safely given in low‐intermediate risk MDS and may be effective in a significant proportion of these patients.

Pamidronate Reduces Skeletal Events but does not Improve Progression-free Survival in Early-stage Untreated Myeloma: Results of a Randomized Trial

Abstract Ninety patients with untreated, stage I-II A myeloma, were randomised to receive or not monthly infusions of pamidronate (PMD) for 1 year, without additional therapies. Follow-up ranged from 36 to 72 months (median 51 months). Three years after the start of the treatment, the disease had progressed in 25% of PMD treated patients and in 26.8% of controls (p n.s). Median time-to-progression was 16 and 17.4 months, respectively (p n.s). Among the 21 patients who required chemo-radiotherapy, skeletal events (osteolytic lesions, pathological fractures and/or hypercalcemia) developed in 9/11 (81.8%) controls and in 4/10 (40%) of treated patients (p < 0.01). “Prophylactic” administration of PMD may decrease the development of skeletal events, but does not reduce the rate and the time of disease progression in early-stage myeloma.

Efficacy of a single, weekly dose of recombinant erythropoietin in myelodysplastic syndromes.

Summary. Thirteen patients with low‐to‐intermediate risk myelodysplastic syndrome (MDS) received recombinant erythropoietin (r‐EPO) at the single, weekly dose of 40·000 U for at least 8 weeks. Five patients (38·4%) achieved a major erythroid response (increased haemoglobin levels > 2 g/dl and/or transfusion independence), which is currently maintained after 3–11 months, without modification of r‐EPO dose. This study suggests that 40·000 U r‐EPO given once a week may be at least as effective as the more frequent (daily or three times a week) administrations of the drug usually employed in MDS patients.

Short progression‐free survival in myeloma patients receiving rituximab as maintenance therapy after autologous transplantation

undergoing PBSCT (using the same protocol, but without anti-CD20 antibody) was 38 months (unpublished observations), we considered these results unacceptable and the trial was stopped. Salvage therapy with single or multiple additional PBSCT (using a melphalan dose of 100 mg/m 2 ) or with a combination of thalidomide, dexamethasone and zoledronic acid, enabled a second remission to be achieved in all cases. Although the number of patients is too low to draw definitive conclusions, in our experience the use of rituximab as maintenance therapy after PBSCT was associated with an unexpectedly high rate of early relapse in MM patients. Recently, a case of plasma cell leukaemia treated with autologous transplantation and early relapse after consolidation therapy with anti-CD20 antibody, has been reported (Gemmel et al, 2002). The reasons of these findings are not clear. We hypothesize a possible role for rituximab in provoking a further decrease in the residual, normal B-cell activity within the context of the complex immunological network characterizing anti-tumour immune response. The therapeutic role of rituximab in MM remains elusive and requires ad hoc studies.

Heterogeneity of response to imatinib-mesylate (glivec) in patients with hypereosinophilic syndrome: implications for dosing and pathogenesis.

Four cases of hypereosinophilic syndrome (HES) treated with the tyrosine-kinase inhibitor imatinib-mesylate are reported. The drug was effective in three patients, but a prolonged clinical and hematological remission was obtained only in one patient, due to appearance of resistance or poor tolerability in the other cases. The dose of imatinib necessary to achieve a response ranged from 100 to 600 mg/d. One patient with evidence of a clonal T-cell population did not respond at all. We confirm the efficacy of imatinib in HES, but we also underline that type and duration of response may be variable. This could be due to different pathogenetic mechanisms of the disease in single patients.

Prognostic relevance of serum thymidine kinase in primary myelodysplastic syndromes: relationship to development of acute myeloid leukaemia

The aim of this study was to evaluate the possible prognostic relevance of thymidine kinase serum levels (s‐TK), an indirect marker of proliferative activity, in myelodysplastic syndromes (MDS). S‐TK levels were monitored by means of a radioenzyme assay in 90 patients affected by MDS (22 refractory anaemia, RA; 17 RA with ring sideroblasts, RARS; 21 RA with blast excess, RAEB; 15 RAEB in transformation, RAEB‐T; 15 chronic myelomono‐cytic leukaemia, CMMoL). Mean s‐TK levels (U//tl) measured at diagnosis were 11–9 –12–6 for RA, 11–4–13′6 for RARS, 19–9 – 28–4 for RAEB, 39–6 – 34–3 for RAEB‐T and 77–7 – 69–7 for CMMoL (normal values <5U//LI1). With the only exception of a weak relationship with lactate dehydrogenase, no correlation was found between initial s‐TK values and other clinical or laboratory parameters, such as age, haemoglobin, white blood cell or platelet count, percentage of bone marrow blasts. MDS patients with s‐TK >38 V/fA, a cut‐off level selected by means of ROC statistical analysis, showed a significantly shorter survival than those with s‐TK <38U//xl (8–2 v 37–4 months, respectively; P < 0–0001). In particular, transformation in acute myeloid leukaemia (AML) occurred in 17/21 (81%) of patients with s‐TK >38U//d and 9/69 (13%) of those with lower levels at diagnosis (P < 00001), independently of FAB subtype. High s‐TK levels were also useful to predict evolution in AML during the course of the disease in patients with normal initial values. Multivariate analysis confirmed the independent prognostic value of s‐TK on both overall survival and risk of acute transformation. We conclude that s‐TK may be an important prognostic factor in MDS, strongly correlated with development of AML.

Serum Beta2-Microglobulin in Malignant Lymphoproliferative Disorders

Beta2-microglobulin (B2m) was measured on serum samples in 274 patients with acute and chronic lymphoproliferative disorders (85 non-Hodgkin lymphomas - NHL, 30 Hodgkin lymphomas - HL, 34 B-cell chronic lymphocytic leukemias - B-CLL, 8 Waldenström macro-globulinemias - WM, 76 multiple myelomas - MM, 31 acute lymphoblastic leukemias - ALL, 10 hairy cell leukemias - HCL). Two hundred and four patients were studied at the time of diagnosis, and results were correlated to clinical stage, and histologic subtype in NHL, immunoglobulin type in MM, and immunologic phenotype in ALL. Moreover, B2m was tested during and after chemo- and/or radiotherapy, and results were correlated to response, progression or relapse. Elevated pretreatment B2m values were found in widespread forms of NHL and HL, in patients with B symptoms and in the unfavorable histologic subgroups of NHL. Rapid falls in levels followed therapy institution. In B-CLL and in MM a close relationship between B2m and cell mass was found. A significant B2m level reduction followed treatment, whereas its increase could detect a relapse. In ALL, serum B2m was only slightly above the normal range. B2m seems to reflect the total burden of malignant cells mainly in MM and B-CLL; in other lymphoproliferative disorders it provides less prognostic information.

Tetraploidy (92,XXYY) in an acute nonlymphocytic leukemia (M1) patient following autologous bone marrow transplantation

Tetraploidy (4n = 92) without structural chromosome aberrations was found in bone marrow cells of a patient with acute nonlymphocytic leukemia, FAB classification M1, following autologous bone marrow transplantation. This finding, which remained undetected during the remission phases and appeared at relapses, progressed to a hypotetraploid modal number (74 chromosomes) at the terminal phase of the disease. Together with two previous observations in patients with acute lymphoblastic leukemia with L2 morphology and a null cell immunotype, this observation supports the hypothesis that tetraploid karyotypes may represent unusual and aspecific patterns of clonal evolution.

Symptomatic myopathy during interferon alfa therapy for chronic myelogenous leukemia.

We report an unusual and serious complication in a patient with chronic myeloid leukemia (CML) undergoing alfa-interferon treatment. A 26-year-old man, suffering from Philadelphia chromosome (Ph)-positive CML, had been treated for 23 months with recombinant interferon alfa (IFNa), administered at 9 million IU daily. A minor cytogenetic response was obtained in the 12th month of therapy (Ph+ 76%). The patient was admitted to our hospital in March 1996, because of the appearance of pharyngodynia, dysphonia, widespread myalgias, dysphagia and symmetric muscle weakness of the extremities. The IFNa therapy had been stopped in the previous week because of fever. During the physical examination we noted a deficiency of velum palatinum and hypotrophy of face and tongue muscles, and in addition, a reduction of chest expansion and a reduction of muscular strength. Blood profiles showed increased alanine aminotransferase (ALT) at 867 IU/l (normal ,60), aspartate aminotransferase (AST) 827 IU/l (normal ,63), lactate dehydrogenase (LDH) 2318 IU/l (normal ,460) and creatine kinase (CK) 17039 IU/l (normal ,195) with 98% of striated muscle-type isonzyme. Magnetic resonance imaging of the brain showed no alterations. Electroneurography was also normal. Electromyography showed myopathic abnormalities. Deltoid muscle biopsy showed lymphocytic and monocytic infiltrates, inequality of fiber size and some muscle necrosis areas, suggestive of polymyositis. Rheumatoid factor, serum Creactive protein and antinuclear antibodies were negative. Serum anti-HCV antibodies were also negative. Peripheral blood count was normal without immature peripheral cells and the chronic phase of the disease was confirmed by bone marrow examination. Respiratory muscle became progressively weaker and because of an increase of Pa CO2 on the 7th day, the patient was transferred to the intensive care unit for mechanical ventilation, and gastrostomy was required as well due to inability to swallow. The methyl-prednisolone therapy was started at 150 mg daily and plasma exchange was performed for 4 days without any improvement. Although serum CPK returned to normal levels on the 17th day, the recovery of autonomous breathing was achieved only after 12 months, when the patient was discharged from the hospital with a slight muscle weakness of the extremities. The CML was still in its chronic phase and treated with hydroxyurea. We have described a very serious case of polymyositis, where the level of CK increased to 90 times the normal,