We read with interest the article on the evidence for increased angiogenesis in the bone marrow of patients with acute myeloid leukemia (AML).1 The observation that increased microvessel density in the bone marrow may play a role in the pathogenesis and thus be a target for future antiangiogenic therapies is promising. But the article lacks the following important prognostic information to accurately predict the significance of their findings. Their study did not take into account well-documented independent adverse prognostic features of AML currently utilized in predicting a response to induction chemotherapy: (1) unfavorable karyotype and (2) white blood cell (WBC) count greater than 20 × 109/L at presentation.2
It would be of extreme importance to determine whether or not the finding of increased angiogenesis adds to the above mentioned adverse prognostic indicators. In particular, we would like the authors to clarify the relationship of increased microvessel density to cytogenetic findings. Did the 25% of patients who had the 2- to 3-fold increase in angiogenesis belong to a good prognostic cytogenetic group such as inv(16), t(8;21), or the well-known favorable karyotype of t(5;17) relating to acute promyelocytic leukemia?3Stratification of results based on favorable, intermediate, or poor prognostic features would be of importance to analyze if increased angiogenesis is an independent prognostic factor.
Clarification of these findings will help determine whether markers of angiogenesis should be utilized in routine diagnosis of AML and will add to the already-known prognostic markers that predict response to therapy. Such information will allow stratification of patients at their initial diagnosis to determine whether or not they should receive conventional chemotherapy alone or should be considered candidates for high-dose therapy followed by stem-cell transplantation or additional experimental approaches, including antiangiogenic therapies.
Angiogenesis and prognosis in acute myeloid leukemia
In their letter, Drs Reddy and Moreb have apparently interpreted our data as indicating that increased angiogenesis is an adverse prognostic factor in acute myeloid leukemia (AML).1-1 But we did not conclude this from our study. Our investigation has unequivocally demonstrated a significant increase of bone marrow microvessel density in 62 patients with newly diagnosed, untreated AML, as compared with control patients. The bone marrow of 75% of the patients (not 25% as stated by Drs Reddy and Moreb) with AML showed a 2- to 3-fold higher microvessel count than the median of the control group. Furthermore, after induction chemotherapy, we observed a significant decrease in microvessel density on day 16 and in complete remission compared with presentation. These findings support the hypothesis of an important role of angiogenesis in AML. Therefore, we disagree with the authors of the letter that information on well-known prognostic factors is essential for the significance of our findings.
Indeed, we investigated whether bone marrow angiogenesis at diagnosis predicts response to induction chemotherapy. For this purpose, a subgroup of 45 patients was chosen. This group was selected because these patients did not have secondary AML, did not die during treatment-induced bone marrow hypoplasia, and received standard induction chemotherapy.1-2 Microvessel counts in bone marrow biopsies at presentation were slightly higher in specimens from patients not achieving a complete remission after induction chemotherapy, as compared with those achieving a complete remission. But the difference was not statistically significant (P = .147). Thus, hitherto there is no evidence from our data that the degree of angiogenesis is of prognostic value. Therefore, we did not yet analyze the relationship of microvessel density with known adverse prognostic factors such as unfavorable karyotype or a white blood cell count greater than 20.0 × 109/L.1-3
We fully agree with Drs Reddy and Moreb that it is important to evaluate whether increased angiogenesis is an independent prognostic factor in AML, as it has been demonstrated for various solid tumors. The lack of statistical significance in our report may be due to the small number of patients who did not achieve a complete remission after induction chemotherapy (n = 12). Therefore, we further pursue this question by studying additional patients for known adverse prognostic factors and will report on this. Furthermore, we are in progress of analyzing the prognostic value of microvessel density at presentation for event-free and overall survival. As long as the prognostic value of the degree of angiogenesis has not been demonstrated in AML, we do not see any role for routine determination of microvessel density or even stratification for experimental therapeutic approaches.
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