BIBLIOGRAFIA
THALIDOMIDE IN PATIENTS WITH MYELOFIBROSIS WITH MYELOID METAPLASIA. - ABSTRACT
MYELOFIBROSIS: REPORT OF FIVE CASES TREATED WITH THALIDOMIDE. - ABSTRACT
Pier Paolo Piccaluga, Carlo Finelli, Paolo Ricci, Michele Cavo, Stefano Aldo Pileri, Alessandro Isidori, Michele Malagola, Tiziana Grafone, Sante Tura, Giuseppe Visani (Intr. by Sante Tura). Institute of Hematology and Clinical Oncology "L&A Seragnoli", University of Bologna, Bologna, Italy. ANTIANGIOGENIC THERAPY WITH THALIDOMIDE IMPROVES ANEMIA, THROMBOCYTOPENIA, HYPERLEUCOCYTOSIS, SPLENOMEGALY IN IDIOPATHIC MYELOFIBROSIS.
Monday, December 4, 2000, 10:00 AM, Hall C, Poster Board Number 688
Increased vascularity and elevated plasma VEGF and bFGF levels have been reported in idiopathic myelofibrosis (IMF). Thalidomide has shown antiangiogenic activity in multiple myeloma patients and should be useful also in IMF.
We thus studied 7 patients (5 male, 2 female), mean age 63 years, with a mean duration of disease of 11 years. In 5/7 cases hystopathological diagnosis was IMF stage IV, in 2/7 cases stage III. CD34 and antiFVIII-antibody were tested in order to estimate vascularity. Two cases showed positivity for CD34. All cases were negative for antiFVIII-Ab. All patients have not been improved their conditions in the last three months with standard therapies (Hydroxiurea, Vinblastine, Androgens and corticosteroids) and common feature to all cases was the progressive increase of splenomegaly. Anemia was present in 6/7 cases (Hb 5.9-12.3 g/dl), thrombocytopenia in 4/7 (46-135 x 109/l), hyperleucocytosis in 3/7 (19.1-40.9 x 10 9/l), splenomegaly in 7/7 (9-25 cm at US scan).
Thalidomide was administered at increasing daily doses from 200 to 600 mg. An intention to treat analysis was performed. No increase of organomegaly was observed in all patients; in particular spleen size decreased in two pts, whereas an improvement of abdominal discomfort was referred in one other case; improvement of anemia was observed in 2/6 (one is now transfusion independent), resolution of thrombocytopenia in 2/4 and reduction of hyperleucocytosis in 2/3 pts. No progression of disease was seen during the treatment in any case.
Side effects were frequent, although mild. Moderate stipsis was observed in 5/7 pts, abdominal disconfort in 2/7, fatigue in 1, sonnolence in 4/7, edema in 2/7, paresthesia in 1/7, dizziness in 1/7.
We conclude that thalidomide is a feasible therapy for IMF and looks useful at least to control the growth progression of the disease.
Keywords: Thalidomide; Myelofibrosis
THALIDOMIDE IN PATIENTS WITH MYELOFIBROSIS WITH MYELOID METAPLASIA.
G. Barosi, A. Grossi, B. Comotti, M. Marchetti. Laboratory of Medical Informatics, IRCCS Policlinico S. Matteo, Pavia, Italy; Hematology and Oncology Unit, Policlinico S. Pietro, Ponte San Pietro, Bergamo, Italy; Division of Hematology, Policlinico Careggi, Florence, Italy.
Monday, December 4, 2000, 10:00 AM, Hall C, Poster Board Number 687
There is evidence of neoangiogenesis in Myelofibrosis with Myeloid Metaplasia (MMM). We report the preliminary experience with the antiangiogenetic drug Thalidomide to assess its efficacy and tolerance. We considered eligible patients with MMM not responsive to standard treatment and with a disease classifiable as high or intermediate risk according to Hb and WBC count (Dupriez prognostic score). Low risk patients were also eligible if splenomegaly extended more than 10 cm from the costal margin, or platelet count were lower than 150 x109/L. They were treated with oral Thalidomide at an escalating dose from 100 to 400 mg/day. Fifteen patients were enrolled, 8 males, with a median age of 64 years, range from 41 to 81 years. Four patient fell in low risk category, 7 in intermediate risk and 2 in high risk. Median time from the diagnosis was 60 months, range from 9 to 216 months. Overall, the patients received the drug for a median duration of 34 days from the first administration (range from 2 to 120 days). Three patients discontinued the drug before completing 15 days of treatment. The causes of early discontinuation were: swelling of tongue (1), nausea (1) and somnolence (1). Ten other patients discontinued the drug after a median time of 31 days, range from 17 to 114 days, for somnolence (3), severe leukopenia (2), dizziness (2), blast transformation (1), muscle rigidity (1), mental deterioration (1). Of the 7 evaluable patients (who received more than 30 days of therapy), anemia improved (Hb increased of more than 1 g/dL or transfusion need reduced) in 2 (28%), splenomegaly reduced (more than 2 cm) in 5 (71%). An undesired platelet count increase was observed in 4 patients (from a range of 113-266 x109/L before treatment to a range of 420-586 x109/L at the end of treatment). Two of these patients had a concomitant increase of LDH (from 2109 mU/ml to 3159 mU/ml and from 990 mU/ml to 2174 mU/ml). Responders took 100 mg (3), 200 mg (2) and 400 mg (1). In conclusion, this study documents that standard dose Thalidomide in MMM patients is burden by high rate of side effects that prevent prolonged treatment. Since the drug is effective in reducing splenomegaly or improving anemia in most of the patients that tolerate the drug, low-dose therapy warrants evaluation. The unexpected observation of mild thrombocytosis and LDH increase, claims biological studies to better understand the mechanism of action of the drug.
Keywords: Myelofibrosis; Thalidomide
MYELOFIBROSIS: REPORT OF FIVE CASES TREATED WITH THALIDOMIDE.
Letizia Canepa, Filippo Ballerini, Riccardo Varaldo, Raffaella Grasso, Marino Clavio, Maurizio Miglino, Ivana Pierri, Marco Gobbi (Intr. by Angelo Michele Carella).
Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem cell disorder including idiopathic and associated (postthrombocythemic and postpolycythemic) myeloid metaplasia. The only chance for achieving a cure in MMM is high doses chemotherapy followed by allogeneic transplantation, but the high median age of the patients at presentation precludes them from this possibility. Immunological and angiogenetic factors are supposed to play an important role in the pathogenesis of the disease. MMM shows biological features indicating disruption of the immune response (Coombs positive hemolytic anemia, antinuclear antibodies,lupus-type anticoagulant),whereas angiogenesis could act through the positive relationship between leukemic and endothelial cells for the production of mutually mitogenic growth factors.Recently trials have been reported regarding use of thalidomide in several hematological malignancies. Thalidomide appears inhibit angiogenesis and alphaTNF production.Three patients (pts) with idiopathic myelofibrosis (iMF) and two with other myeloproliferative disorders with associated MF (aMF) were treated with thalidomide, starting with 200 mg/die and increasing by 100 mg every two weeks, according to tolerance and response. Two iMF pts were therapy naive, whereas the other three (1 iMF and 2 aMF) failed to respond to previous therapy. All pts showed hepatosplenomegaly and three were transfusion dependent (all iMF pts). One patient had abnormal karyotype (47,XY,+8).
Two iMF patients with Hb levels <8 g/dl before therapy, became transfusion independent and experienced significant reduction in splenomegaly and marked improvement in platelets an WBC levels. Both have been assuming therapy since 8 months and the actual dose is 400 mg, with mild side effects including somnolence and constipation. The third iMF patient developed haemolityc anemia requiring splenectomy, before any response to thalidomide could become evident.Both aMF patients do not show hematologic improvement at the dose of 400mg/die, despite the time on thalidomide is four months.In conclusion, in the dose range of 200-400mg/die thalidomide was relatively well tolerated in our patients, with grade 0-1 WHO toxicity. Side effects included somnolence, constipation and dry mouth. Our data suggest the possibility that thalidomide could have a substantial efficacy in previously untreated idiopathic myelofibrosis (probably in early proliferative phase), whereas failure has been observed in MPD associated myelofibrosis.
Keywords: Thalidomide; Myelofibrosis
Am J Med 2000 Apr 15;108(6):487-95. Thalidomide: current and potential clinical applications. Calabrese L, Fleischer AB. Department of Rheumatic and Immunologic Disease, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, USA. - http://www-east.elsevier.com/ajm/main.html
Curr Opin Oncol 2000 Nov;12(6):564-73 Current role of thalidomide in cancer treatment. Thomas DA, Kantarjian HM. University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston 77030, USA. debthomas@mdanderson.org - http://www.co-oncology.com/