2006_10

CDKN2A FISH analysis of Ewing sarcoma. Cytogenet Before treatment, 7 patients (47%) were transfusion 9. Scheinin I, Myllykangas S, Borze I, Bohling T, Knuutila S, dependent (mean requirement 5.9 units over six Saharinen J. CanGEM: mining gene copy number changes months, range 0–21); 6 had platelet counts < 100×109/L in cancer. Nucleic Acids Res Epub 2007 Oct 11.
(mean 157×109/L, range 32–487×109/L). All non- 10. Panani AD. Cytogenetic and molecular aspects of Philadelphia negative chronic myeloproliferative disor- splenectomized patients had palpable splenomegaly ders: clinical implications. Cancer Lett 2007;255:12-25.
11. Espinet B, Puigdecanet E, Florensa L, González L, Salido After low dose thalidomide ±prednisolone the over- M, Bellosillo B, et al. Array comparative genomic hybridization reveals an absence of recurrent genomic all transfusion requirements were unchanged (mean 6.0 copy number changes in essential thrombocythemia.
units/six months), 3 out of 7 (43%) transfusion-depend- Abstract 0098. Haematologica (EHA Annual Meeting ent patients had a fall in transfusion requirement after thalidomide, 2 became transfusion independent.
However, 3 patients progressed and required transfu-sion. There was no significant rise in mean platelet Low-dose thalidomide in myelofibrosis
counts (157×109/L pre-treatment, 184×109/L post-treat-ment). Splenomegaly was reduced by more than 50%in 4 out of 13 (31%) patients. Median white cell count Allogeneic stem cell transplant is the only potentially curative treatment for myelofibrosis, but is often pre- Overall responses according to EUMNET criteria cluded by advanced age, poor performance status or were: no complete responses, five major responses copathologies.1 Increased marrow angiogenesis occurs (33%), one moderate response (7%), and five minor in myelofibrosis and greater neovascularization corre- responses (33%). Four patients (27%) had no response.
lates with poorer prognosis,2 stimulating interest in Median time to peak response was 7.5 weeks (range thalidomide therapy. Doses of 100-400mg daily 2–15 weeks). Seven patients both had a response and reduced transfusion requirement and splenomegaly in did not stop thalidomide early because of adverse some patients, but were poorly-tolerated.3 Low-dose effects; the median response duration was 16 weeks thalidomide starting at 50mg daily with/without a (4–95 weeks). For 3 patients, response was lost when tapering dose of prednisolone is reported to be well-tol- prednisolone stopped at week 12. The 2 patients not treated with prednisolone demonstrated a minor and We investigated 15 patients treated with low-dose no response respectively. Five out of 13 patients (38%) thalidomide (50 mg daily) for myelofibrosis in our cen- were positive for the JAK2V617F mutation and were ters. The study was approved by the ethics committee at indistinguishable from negative patients.9 St Thomas’ Hospital. All patients met consensus criteria Four patients (27%) developed grade 1/2 peripheral for myelofibrosis.6 Clinical parameters are summarized neuropathy; 2 grade 1/2 constipation while somno- in Table 1. Median follow-up was eight months.
lence was reported in one patient. No proven throm- All patients initially received oral thalidomide 50 mg boembolism occurred, but one patient with pneumonia daily. Thirteen patients also received oral prednisolone and marked leukocytosis died following an uncon- at 30-60 mg (0.5-1mg/kg) daily; tapered over 12 weeks.
firmed pulmonary embolism. There was no neutrope- Responses were confirmed according to European nia or increased myeloproliferation. One patient expe- Myelofibrosis Network (EUMNET) criteria;7 the rienced weight gain and folliculitis ascribed to steroids.
International Working Group consensus criteria8 were Eleven patients had stopped thalidomide by the end of not used since no patient had repeated bone marrows. the study due to: lack/loss of hematologic response Table 1. Patients’ characteristics and responses.
ET: essential thrombocytosis; PV: polycythemia vera; F: female; M: male; HU: hydroxycarbamide (hydroxyurea); IFNα: interferon α; EPO: erythropoietin. Lille score: Dupriez et al., 1996. EUMNET response criteria: Barosi et al., 2005. (n=6), neuropathy (n=3), development of an unrelatedmalignancy (glioblastoma) (n=1), reduced-intensity References
1. Cervantes F. Modern management of myelofibrosis Br J This is the first study to use internationally agreed response criteria for myelofibrosis (the EUMNET crite- 2. Mesa RA, Hanson CA, Rajkumar SV, Schroeder G, Tefferi ria) to evaluate response to thalidomide and pred- A. Evaluation and clinical correlations of bone marrow nisolone. Overall, 40% of patients achieved major or angiogenesis in myelofibrosis with myeloid metaplasia.
moderate responses by EUMNET criteria. All respons- 3. Elliott MA, Mesa RA, Li CY, Hook CC, Ansell SM, Levitt es began within the first 12 weeks of treatment, sug- RM, et al. Thalidomide treatment in myelofibrosis with gesting that thalidomide could be stopped if there is no myeloid metaplasia. Br J Haematol 2002;117:288-96.
4. Mesa RA, Steensma DP, Pardanani A, Li CY, Elliott M, response by this time. Among responders, the median Kaufmann SH, et al. A phase 2 trial of combination low- response duration was 16 weeks. Three patients lost dose thalidomide and prednisone for the treatment of their responses when prednisolone was withdrawn at myelofibrosis with myeloid metaplasia. Blood 2003; 101: 12 weeks. The 2 patients not treated with prednisolone 5. Marchetti M, Barosi G, Balestri F, Viarengo G, Gentili S, appeared to have a less favourable response.
Barulli S, et al. Low-dose thalidomide ameliorates cytope- Our results are consistent with those of phase II tri- nias and splenomegaly in myelofibrosis with myeloid als.4 In the Mesa trial,4 40% became transfusion inde- metaplasia: a phase II trial J Clin Oncol 2004;22:424-31.
6. Barosi G, Ambrosetti A, Finelli C, Grossi A, Leoni P, pendent, 75% had a >50% rise in platelet count, and Liberato NL, et al. The Italian Consensus Conference on 19% had a >50% reduction in spleen size. In the Diagnostic Criteria for Myelofibrosis with Myeloid Marchetti trial,5 39% became transfusion independent, Metaplasia. Br J Haematol 1999;104:730-7.
7. Barosi G, Bordessoule D, Briere J, Cervantes F, Demory JL, 22% had a >50x109/L rise in platelet count, and 19% Dupriez B, et al. Response criteria for myelofibrosis with had a >50% reduction in spleen size.
myeloid metaplasia: results of an initiative of the The relative importance of thalidomide and pred- European Myelofibrosis Network (EUMNET). Blood nisolone when used in combination is unclear, but 8. Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly prednisolone seems to be partly responsible for JT, et al. International Working Group (IWG) consensus responses. Case reports suggest that corticosteroids criteria for treatment response in myelofibrosis with have efficacy as monotherapy in myelofibrosis.9 myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood 2006;108: However, our response rates are similar to those obtained with thalidomide monotherapy (median 100 9. Jack FR, Smith SR, Saunders PW. Idiopathic myelofibrosis: mg/d). Three of our patients experienced a loss of clin- anaemia may respond to low-dose dexamethasone. Br J ical response when prednisolone was stopped consis-tent with other studies4 and 2 patients not treated withprednisolone showed a poorer performance.
Our data confirms that low-dose thalidomide with Increased cortical bone mineralization in imatinib
treated patients with chronic myelogenous
prednisolone is effective treatment for myelofibrosis, leukemia
leading to transfusion independence, improvement inthrombocytopenia and reduction in spleen size in somepatients. We recommend assessment of thrombotic risk Imatinib mesylate (Glivec®, Gleevec™, Novartis and thromboprophylaxis for high-risk patients. Low- International AG) and the second generation ABL tyro- dose thalidomide is not effective in all patients, and sine kinase inhibitors have markedly improved the out- responses are often not sustained after withdrawal of come of patients with chronic myeloid leukemia (CML).
More patients are receiving treatment with these inhibitors for prolonged periods of time and experience Robert Weinkove,1 John T. Reilly,2 Mary Frances McMullin,3 with imatinib now exceeds five years. The immediate Natasha J. Curtin,4 Deepti Radia,1 and Claire N. Harrison1 side effects are usually mild and manageable. There have 1Department of Haematology, St Thomas’ Hospital, London; been recent reports on the long-term side effects associ- 2Department of Haematology, Royal Hallamshire Hospital, ated with prolonged use of imatinib.1-3 Berman and co- Sheffield; 3Department of Haematology, Belfast City Hospital, workers found that imatinib treated patients had Belfast; 4Department of Haematology Queen Elizabeth Hospital, hypophosphatemia, lower osteocalcin levels and higher parathyroid hormone levels.2 Subsequent studies con- Acknowledgments: we wish to thank Drs. N. Ketley and J. Ropner firmed the observation of hypophosphatemia in patients receiving imatinib.4-8 The authors concluded that ima-tinib may affect bone remodeling and if left untreated, Correspondence: Claire Harrison, Department of Haematology, St chronic hypophosphatemia may result in impaired bone Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust mineralization, rickets, and osteomalacia.2 London SE1 7EH, UK. Phone: international +44.207.1882742. We, therefore, investigated bone mineral density Fax: international +44.207.1882728. E-mail: [email protected] (BMD) in imatinib treated CML patients and healthycontrols. All imatinib treated CML patients at Citation: Weinkove R, Reilly JT, McMullin MF, Curtin NJ, Radia Sahlgrenska University Hospital were identified of D, Harrison CN. Low-dose thalidomide in myelofibrosis. whom 17 fulfilled the study inclusion criteria: (i) imatinib Haematologica 2008; 93:1100-1101. treatment duration ≥24 months, and (ii) first chronic phase of the disease with complete cytogenetic remis-sion. The inclusion criteria were set to minimize the con-founding effect of leukemia and to allow time for a pos-

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