- Top of page
- Patients and methods
We administered the anti-angiogenic drug thalidomide to 21 patients (12 men) with myelofibrosis with myeloid metaplasia (MMM), who were not responsive to standard treatment. Patients received thalidomide at an escalating dose from 100 to 400 mg/d. Administration of the drug was discontinued before the planned 6 months of treatment in 19 patients (90·5%), mainly because of somnolence and/or fatigue, neurological symptoms or neutropenia. Of the 13 evaluable patients (who received more than 30 d of therapy), anaemia improved in three out of seven (43%) who were treated because of anaemia; thrombocytopenia improved in two out of three (66·6%) who were treated because of thrombocytopenia; splenomegaly was reduced in four (30·8%). Undesired increases in white blood cell and platelet counts were observed in three (23·1%) and five (38·5%) patients respectively. A severity score, indexed on haematological and clinical parameters, improved in two patients (15·4%), but worsened in five (38·5%). In conclusion, standard-dose thalidomide in MMM patients is burdened with a high rate of side-effects, which prevent prolonged treatment. Because the drug is effective in improving anaemia and thrombocytopenia and in reducing splenomegaly, low-dose therapy warrants evaluation. The unexpected observation of leucocytosis and thrombocytosis suggests biological studies and better criteria for selection of patients for treatment.
Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder characterized by native bone marrow fibrosis and extramedullary haematopoiesis (Barosi, 1999). At present, ablation of the abnormal haemopoietic clone with high-dose chemotherapy followed by allogeneic stem cell transplantation provides the only chance of achieving a cure in MMM (Guardiola et al, 1999). Traditional treatments with androgens to sustain erythropoiesis, and cytostatics to slow down the progression of splenomegaly and splenectomy, in selected cases, provide poor control of disease progression. Therefore, the disease is burdened with high morbidity and mortality, and alternative effective approaches are warranted.
In recent years, there has been a renewed interest in thalidomide, a drug with anti-angiogenic and immunological effects (D'Amato et al, 1994; Hales, 1999). The potential therapeutic applications span a wide spectrum of diseases, including infectious, autoimmune and dermatological diseases (Anderson, 2000). Moreover, an anti-tumour effect has been documented in advanced tumours (Fine et al, 2000) and refractory multiple myeloma (Singhal et al, 1999; Yakoub-Agha et al, 2000).
As for MMM, a prognostically detrimental increase in bone marrow microvessel density has been demonstrated (Lundberg et al, 2000; Mesa et al, 2000) and a pilot study with thalidomide has been reported (Thomas et al, 1999). In that preliminary communication, the drug decreased the transfusion need, improved cytopenias and decreased the need for cytoreductive agents in some of the patients. However, toxicity (mainly fatigue, constipation and rash) occurred in the majority of the treated cases.
We report the results in terms of feasibility and objective responses of thalidomide in patients with MMM who had proved refractory to standard therapy.
- Top of page
- Patients and methods
We used thalidomide in MMM patients with the main aim of taking advantage of its anti-angiogenic effect, thus improving the microenvironment and haematopoietic cell maturation in the bone marrow and extramedullary sites. From the experience with thalidomide in other inflammatory and malignant diseases, we used thalidomide at the starting dose of 100 mg. At this dose, 38·1% of the patients discontinued the drug before 30 d of treatment and 76·2% before 3 months. Overall, the drug discontinuation rate was 90·5% before the end of the 6 months of planned therapy. This is quite similar to the discontinuation rate (92%) reported recently in patients treated with thalidomide for chronic graft-versus-host disease (Koc et al, 2000), but lower than reported in most other studies (Singhal et al, 1999; Yakoub-Agha et al, 2000). However, we observed somnolence and fatigue in 52·4%, constipation in 47% and neurological side-effects in 4% of the patients, which are in the range of values reported in the literature. Owing to the open design of the study and the nature of a compassionate-use protocol, the patients were aware of taking a drug possibly charged with side-effects and, particularly, with neurological toxicity. As a matter of fact, with the exception of two cases in which a severe neutropenia induced the physician in charge to stop the drug, patients themselves requested to stop treatment because of side-effects. It is possible that patients enrolled in previously published studies had considerably more encouragement and support than we gave to sustain compliance with a regimen of thalidomide at even higher doses.
In this study, the response to treatment was evaluable in only 13 (62%) of the patients. In eight of them (61·5%), some response was evidenced as improvement in anaemia, correction of thrombocytopenia, reduction in leucocytosis and/or reduction in spleen volume. However, when these effects were measured using a ‘severity’ score that accounted for major changes in haematological and clinical parameters, only two patients (15·4%) had a score reduction and were classified as responders.
An unexpected and undesired increase in WBC and/or platelet count, associated with increased serum LDH levels, occurred in seven patients. Such changes caused the ‘severity’ score to increase by 1–2 points (out of 6) in five of these patients. This result confirms an observation reported recently by Tefferi & Elliott (2000) of drug-related steep increases in platelet and leucocyte counts in three patients with MMM. In our study, the increase in peripheral cell count was moderate and not associated with disease complications. In only one patient, who extended treatment because of a beneficial effect on anaemia, were changes associated with an increase in spleen volume. In contrast, Tefferi & Elliott (2000) documented a rise in platelet count up to more than 1000 × 109/l and the development of pericardial effusion secondary to extramedullary haematopoiesis in one patient. The mechanism of this detrimental activity of thalidomide remains to be determined. However, in two of our patients we were able to document a steep rise in the number of circulating CD34+ cells that paralleled the increase in the circulating mature cells. Circulating CD34+ cells are constitutively elevated in MMM and their number reflects the myeloproliferative characteristic of the disease (Barosi et al, 2000). This leads to the conclusion that thalidomide may act by inducing myeloproliferation in MMM. This is also surprising considering that in other patients we documented a reduction in the number of WBC, and changes in both the myeloproliferative and myelodepletive indexes. The immunosuppressive and anti-inflammatory action of thalidomide, which inhibits the production of tumour necrosis factor α (TNF-α) (Klaushner et al, 1996), and a possible direct antiproliferative action of the drug on tumour cells, as documented in myeloma cells (Hideshima et al, 2000), could explain these different effects.
In conclusion, the results of this study show that standard-dose thalidomide treatment in MMM is burdened with a high number of side-effects that limit its long-term use. However, the drug acts by both improving and worsening the clinical and haematological picture of the disease. The possible myeloproliferative effect of thalidomide requires biological studies in order to better understand the mechanism of action of the substance and for better targeting of the therapy. Prospective trials are required to delineate the role of this drug in MMM, and also to document whether low-dose treatment may be effective and well tolerated. The reported experience with low-dose treatment in neoplastic and non-neoplastic diseases suggests that a dose of 50 mg/d as a starting dose may be both effective and well tolerated (Larkin, 1999; Vasiliauskas et al, 1999; Kyriakis et al, 2000).