The Prognostic Significance of Pretreatment Marrow Fibrosis in Imatinib-Treated CML
The Prognostic Significance of Pretreatment Marrow Fibrosis in Imatinib-Treated CML
Abstract & Commentary
By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC and is Editor of Clinical Oncology Alert. Dr. Ershler is on the speaker’s bureau for Amgen and does research for Ortho Biotech.
Synopsis: Imatinib mesylate treatment has dramatically altered clinical outcomes for patients with CML and the question has arisen whether those prognostic factors shown to be relevant in the pre-imatinib era remain so today. This report from M.D. Anderson would suggest that although treatment responses have improved across the board, bone marrow fibrosis remains a significant indicator of lower treatment response and shorter survival.
Source: Kantarjian HM, et al. Significance of myelofibrosis in early chronic-phase, chronic myelogenous leukemia on imatinib mesylate therapy. Cancer. 2005;104:777-780.
Myelofibrosis, present in approximately 40% of patients at the time of diagnosis, is known to have negative prognostic implications.1 Accordingly, the degree of fibrosis correlates strongly with treatment response and survival.
Imatinib mesylate, a tyrosine kinase inhibitor has greatly influence treatment responses and overall survival for CML patients. Treated patients attain cytogenetic complete response in 70-90% of the time2 and many of these will achieve major molecular remission (ie, disappearance of the Bcr-Abl abnormality).3 Median survival for newly diagnosed CML patients is now expected to be approximately 15 years.
Thus, imatinib has become first line treatment producing dramatic cytogenetic response ranging anywhere from 70-90% as measured by quantitative polymerase chain reaction.
Prior concerns about myelofibrosis in CML patients were reported before the imatinib era. The goal of the current study was, by retrospective analysis, to evaluate the significance of bone marrow fibrosis in those patients being treated with imatinib as first-line therapy. Patients (n = 198) evaluated and treated at the University of Texas M.D. Anderson Cancer Center (Houston) ranging from 16-84 years of age, with Ph1-chromosome-positive chronic phase CML, were stratified into four subgroups based on the degree of reticulin fibrosis found in their bone marrow. The prevalence of myelofibrosis in this group (38%) was found to be similar to prior reports.1,4
Grade 3-4 fibrosis was associated with significantly higher incidences of other adverse factors (eg, basophilia) or for trends of such associations (eg, older age, anemia, and splenomegaly). There was a trend towards lower incidence of a complete cytogenetic response in patients with Grade 4 reticulin fibrosis compared to those with absent or lower Grade fibrosis (76% vs 89%; P = 0.07) and a significantly worse survival (estimated 3-year survival rate of 87% vs 97%; P = 0.04).
Commentary
There has been a dramatic change in the outlook for patients with CML, and this is attributed to the introduction of imatinib therapy. Prognostic factors, such as age, splenomegaly, and the presence of myelofibrosis were found to be of value in selecting those patients who might require or benefit from more intensive therapy (eg, marrow or stem cell transplant) early in the disease course. Although the current report is far from definitive (retrospective, single institution, etc), it appears those same prognostic factors remain statistically significant, although they may not impart the same clinical importance. In this regard, it is gratifying to note that even those patients with advanced fibrosis had a 76% cytogenetic complete response and estimated 3 year survival of 87%; far superior to the pre-imatinib era. Thus, those factors that were earlier shown to influence clinical outcomes reflect a more aggressive biology, and imatinib appears to be comparably effective even under more adverse circumstances (such as with advanced fibrosis, but also older age, or in the presence of anemia, splenomegaly and thrombocytosis). This, raises the question of to whom and when should alternative treatments, such as allogeneic transplant be offered.
References
1. Dekmezian R, et al. The relevance of reticulin stain-measured fibrosis at diagnosis in chronic myelogenous leukemia. Cancer. 1987;59:1739-1743.
2. Goldman J, Melo J. Chronic myeloid leukemia--advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451-1464.
3. Kantarjian H, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood. 2004;103:2873-2878.
4. Buesche G, et al. Marrow fibrosis, indicator of therapy failure in chronic myeloid leukemia—prospective long-term results from a randomized-controlled trial. Leukemia. 2003;17:2444-2453.
Imatinib mesylate treatment has dramatically altered clinical outcomes for patients with CML and the question has arisen whether those prognostic factors shown to be relevant in the pre-imatinib era remain so today. This report from M.D. Anderson would suggest that although treatment responses have improved across the board, bone marrow fibrosis remains a significant indicator of lower treatment response and shorter survival.Subscribe Now for Access
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