Clinical Leukemia最新文献

In the decade of new therapeutic options for myelodysplastic syndromes (MDS), it is more important than ever to recognize how to diagnose the disease and classify the patients into a subtype or risk stratification that allows predicting prognosis and, more importantly, developing treatment strategy accordingly. The classification of MDS has been an evolving process as we learn more about the disease. In this article, we review the World Health Organization (WHO) classification of MDS, highlighting the major changes compared with the French-American-British classification. We review the validation of the WHO and then discuss the application and difficulties of the WHO classification. We study the International Prognostic Scoring System and its new modification, the WHO prognostic scoring system. Finally, we look to the future, introducing some of the suggested revisions to the WHO classification.

Background

Dasatinib is a potent inhibitor of multiple tyrosine kinases, including Bcr-Abl and Src. Pleural effusions have occurred at an incidence of 21% in phase II studies with dasatinib. We investigated the incidence, clinical course, and management of pulmonary abnormalities in patients receiving dasatinib from 2 Canadian institutions.

Patients and Methods

Between March 2005 and November 2006, 38 patients with Philadelphia chomoseome–positive (Ph⁺) leukemia (chronic myeloid leukemia, n = 36; Ph⁺ acute lymphoblastic leukemia, n = 2) received dasatinib for imatinib resistance (n = 31) or intolerance (n = 7), 35 of whom received a 70-mg twice-daily regimen.

Results

With a median duration of 95 weeks of administration, 17 patients (45%) experienced pulmonary abnormalities, including 16 cases of pleural effusion (grade 1, n = 1; grade 2, n = 11; grade 3, n = 4) and 1 case of a lung parenchyma change (grade 3), with a median time to onset of 4 weeks after start of dasatinib. In total, 51 events were observed. The incidence of pulmonary abnormalities was higher in patients with a history of previous pulmonary disease and imatinib intolerance. Dasatinib therapy was temporarily interrupted in 16 patients, and resolution of the pulmonary abnormalities was evident within 4 weeks. Recurrences occurred within 13 weeks of dasatinib being reinitiated at a lower dose, with a median of 4 recurrence episodes. The development of these pulmonary abnormalities did not adversely affect patient responses to dasatinib.

Conclusion

We conclude that such pulmonary abnormalities are relatively common in patients receiving dasatinib and can have a late presentation (up to 21 months). Temporary dasatinib interruption is the best management strategy once they are recognized. Patients with pulmonary comorbidities and patients intolerant to previous imatinib therapy need to be carefully monitored for the occurrence of these abnormalities during dasatinib therapy.

Spontaneous remission of acute myeloid leukemia (AML) is very rare, with < 100 reported cases in adults. We describe herein 3 patients with AML and 1 with high-risk myelodysplastic syndrome at our institution who had spontaneous remission. Spontaneous remissions are generally of short duration and therefore require close follow-up to detect relapses.

This review provides an overview of the current literature on epidemiologic findings in patients with myelodysplastic syndromes (MDS). Based on the data of local registries and large-scale epidemiologic surveys, the annual incidence of MDS is approximately 4-5 cases per 100,000 people in developed countries. This figure might be underestimated because the diagnosis of MDS in elderly patients presenting with anemia of unknown etiology is often not confirmed because of the reluctance of patients and physicians to perform bone marrow examinations. Because the identification of nonblastic MDS types requires a particular diagnostic expertise, they are not unequivocally discernible from cases of secondary anemia and are therefore probably underrated. There is no evidence of an increasing age-adjusted incidence of MDS, but the absolute number of patients with MDS might increase in parallel with the demographic changes we currently witness. There is only a small number of patients with MDS who have a history of exposure to compounds known for their myelotoxic effects, such as benzene and radiation. Still, approximately 10% of patients with MDS develop the treatment-associated disease as a result of previous cytotoxic chemotherapy, radiation therapy, or a combination of both. The proportion of patients with treatment-associated MDS might increase in the future as a result of better and longer survival times of patients following more effective cancer treatment.

Major advances in the understanding of chronic lymphocytic leukemia (CLL) biology, prognosis, and therapy have drastically changed the management of CLL in the past 2 decades. As a heterogenous disease, approximately two thirds of CLL will eventually progress and require therapy. Cytogenetic aberrations, especially 17p–, 11q–, and the mutational status of the variable region of the immunoglobulin heavy chain gene, are the strongest independent prognostic factors to predict CLL progression. Asymptomatic patients with early-stage disease will need to be risk stratified into low- or high-risk categories for counseling, follow-up, and referral to a clinical trial. Treatment with chemoimmunotherapy is required for patients with CLL with progressive or symptomatic diseases. Progressive diseases with high-risk features in relatively healthy patients might do best with allogeneic stem cell transplantation with reduced-intensity conditioning regimens.

Conventional treatment of myelofibrosis includes a wait-and-see approach for asymptomatic patients, the use of oral cytolytic drugs such as hydroxyurea for the hyperproliferative forms of the disease, androgens or erythropoietin for anemia, and splenectomy in selected patients. Although these treatment modalities can improve quality of life, many patients do not respond, and the impact on survival is scant. This fact has stimulated the search for newer therapies for the disease. Antiangiogenic and immunomodulatory drugs such as thalidomide and lenalidomide have shown efficacy against anemia and thrombocytopenia but have frequent side effects. The combination of low-dose thalidomide with prednisone can also be effective and has a better tolerability. The therapeutic role of imatinib is limited, while tipifarnib, a farnesyltransferase inhibitor, has a modest effect in anemia and splenomegaly. Allogeneic stem cell transplantation (alloSCT) is the only curative therapy of myelofibrosis. AlloSCT with a standard conditioning regimen has an associated mortality rate of 30% and is indicated in younger patients with high-risk disease or resistance to conventional treatment. Because of its low mortality and curative potential, reduced-intensity conditioning alloSCT is being used in patients aged 45-70 years with high- or intermediate-risk myelofibrosis or resistance to treatment. Autologous SCT can be a palliative measure in patients without a suitable donor. The efficacy in myelofibrosis of newer immunomodulatory drugs, including pomalidomide, proteasome inhibitors, hypomethylating agents, and especially, Janus kinase 2 inhibitors, is currently being evaluated.