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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1617-1618
CORRESPONDENCE
To the Editor:
Prognostic correlation of increased angiogenesis in acute
myeloid leukemia with cytogenetics
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?3
Stratification 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.
Vijay Reddy and Jan Moreb
Division of Hematology/Oncology University of Florida
College of Medicine Gainesville, FL
References
1.
Padro T, Ruiz S, Bieker R, et al.
Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia.
Blood.
2000;95:2637-2644[Abstract/Free Full Text].
2.
Lowenberg B, Downing JR, Burnett A.
Acute myeloid leukemia.
New Engl J Med.
1999;341:1051-1062[Free Full Text].
3.
Warrel RP Jr, de The H, Wang Z-Y.
Acute promyelocytic leukemia.
New Engl J Med.
1993;329:177-189[Free Full Text].
Response:
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 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.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.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.
Teresa Padró, Wolfgang E. Berdel, Thomas Büchner, and Rolf M. Mesters
Department of Medicine/Hematology and Oncology University of
Muenster Muenster, Germany
References
1.
Padró T, Ruiz S, Bieker R, et al.
Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia.
Blood.
2000;95:2637-2644.
2.
Büchner T, Hiddemann W, Wörmann B, et al.
Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group.
Blood.
1999;93:4116-4124[Abstract/Free Full Text].
3.
Löwenberg B, Downing JR, Burnett A.
Acute myeloid leukemia.
N Engl J Med.
1999;341:1051-1062.
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