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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Medicine/Hematology and
Oncology, University of Muenster, Germany.
Emerging data suggest an involvement of angiogenesis in the
pathophysiology of acute myeloid leukemia (AML). Thus, antiangiogenic therapy could constitute a novel strategy for the treatment of AML. To
test this hypothesis, a phase I/II dose-escalating trial was performed
to study the safety and efficacy of thalidomide, a putative inhibitor
of angiogenesis, in 20 patients with AML. Thirteen patients
were assessable for both toxicity and response, tolerating a maximum
dose of 200 to 400 mg daily for at least 1 month. Seven patients had to
be prematurely withdrawn from drug administration owing to progressive
disease and death (3 patients), personal decision (2 patients), or
inability to tolerate thalidomide (2 patients). Overall, adverse events
were fatigue, constipation, rash, and neuropathy (grade 1 to 2 in most
patients). In 4 patients, a partial response, defined as reduction of
at least 50% in the blast cell infiltration of the bone marrow
accompanied by increases in platelet counts and hemoglobin values, was
observed. One additional patient showed a hematologic improvement
without fulfilling the criteria of a partial response. The responses
lasted a median of 3 months (range, 1-8 months). In parallel,
microvessel densities significantly decreased in these 5 patients
during treatment with thalidomide (P < .05). This
decrease was accompanied by declining plasma levels of basic fibroblast
growth factor, one of the most potent angiogenic growth factors. In
conclusion, single-agent thalidomide has antiangiogenic and
antileukemic activity in AML, although a causal relationship between
both effects has still to be proven.
(Blood. 2002;99:834-839) Angiogenesis, a complex process of pericellular
proteolysis, endothelial migration, and proliferation, is an absolute
requirement for the viability and growth of solid tumors.1
Recently, we reported increased angiogenesis in the bone marrow of
patients with acute myeloid leukemia (AML) and normalization of bone
marrow microvessel density when patients achieved a complete remission (CR).2 This suggests an involvement of angiogenesis in the pathophysiology of AML as well. Thus, antiangiogenic therapy could constitute a novel strategy for the treatment of AML.
Thalidomide, a derivative of glutamic acid, was introduced in
Europe in 1954 as a sedative/hypnotic agent,3 but was
removed from the market when its teratogenic effects were discovered. Recently, it was demonstrated that thalidomide has potent
antiangiogenic activity in animal models,4,5 possibly
owing to its direct inhibition of endothelial cell
proliferation.6 This prompted the initiation of a number
of clinical trials of thalidomide for the treatment of advanced
malignancies. In contrast to its limited activity reported in advanced
solid tumors so far,7-9 its efficacy in acquired
immunodeficiency syndrome (AIDS)-related Kaposi sarcoma and refractory
multiple myeloma is striking.10,11 However, since
thalidomide has a variety of different modes of action,12 a causal relationship between its antiangiogenic effect and clinical activity against neoplastic diseases has still to be demonstrated.
We conducted a phase I/II dose-escalating study in AML patients not
qualifying for intensive cytotoxic chemotherapy in order to assess the
efficacy and safety of thalidomide in AML.
Study design
Patients were treated with 200 mg/d thalidomide, escalating by 200 mg/d
every 2 weeks until a total dose of 800 mg/d was achieved. Safety was
assessed at least weekly through physical examinations, recording of
vital signs, toxicity assessments, and laboratory tests (hematology,
coagulation, clinical chemistry). Grade 2 toxicities were considered to
be dose limiting, requiring withdrawal from further dose escalation.
Additionally, neurotoxicity of grade 2 required a dose reduction of 200 mg. Persistent grade 2 neurotoxicity lasting more than 6 days after
dose reduction resulted in discontinuation of the study drug. Patients
were taken off the study if they had grade 3 neurotoxicity, other grade
3 toxicity persisting more than 6 days after dose reduction, or any
grade 4 toxicity. Thalidomide was given in the evening to avoid
sedative side effects during daytime. Patients were asked to take
lactulose (Bifiteral, Solvay Arzneimittel, Hannover, Germany) to
prevent constipation.
Evaluation and criteria of response
Measurement of angiogenic growth factors Blood samples for measurements of the circulating angiogenic factors, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) were obtained after 1 month of treatment with thalidomide and quantitatively determined in citrate anticoagulated plasma by enzyme-linked immunosorbent assay (ELISA) (Quantikine human VEGF, Quantikine HS human FGF basic) (R&D Systems, Minneapolis, MN). Owing to the known release of VEGF from platelets,15 venous blood sampling for VEGF measurement was performed within glass collection tubes in the presence of citrate, theophylline, adenosine, dipyridamole as platelet stabilizer (Becton Dickinson Vacutainer Systems, Plymouth, United Kingdom). Tubes were centrifuged at 3000g for 10 minutes at 20°C to generate platelet-poor plasma.16 Aliquots were stored at 70°C until analysis and assayed for each patient on the same ELISA
plate. The normal range (mean ± 1 SD), determined in 25 healthy
volunteers, was 22.5 ± 20.8 pg/mL for VEGF and 9.4 ± 6.4 pg/mL
for bFGF.
Statistical analyses Data are presented as individual data plots or medians with interquartile ranges including low quartile and high quartile (LQ-HQ). Differences in peripheral blood cell counts, percentage of leukemic blasts, and microvessel density in the bone marrow before and after treatment with thalidomide were analyzed by the Wilcoxon matched-pair signed rank test. The Mann-Whitney rank sum test for independent groups was used to compare bone marrow microvessel counts in thalidomide-responding, nonresponding, and control patients. Comparisons of VEGF/bFGF plasma level changes and dose of thalidomide between responders and nonresponders were evaluated by the Fisher exact test. For all tests, P < .05 was considered significant. The 95% confidence intervals were calculated by employing exact binomial confidence limits.
A total of 20 patients aged 58 to 85 years (median, 69 years) were
accrued to the study. Patient and disease characteristics are
summarized in Table 1. Ten patients had
secondary AML defined as a history of myelodysplasia, other antecedent
hematologic disorder, or previous exposure to cytostatic drugs or
radiotherapy. Cytogenetic analyses were available in 13 patients; these
showed prognostically unfavorable chromosomal aberrations in 5 patients, standard-risk cytogenetic abnormalities in 3 patients, and
normal karyotypes in 5 patients. Eleven patients had AML relapse.
Fourteen patients had received prior chemotherapy regimens (4 patients
had received 1 regimen, and 10 patients, 2 or more regimens). Before
starting thalidomide administration, patients had been off previous
therapy for a median of 31 weeks (range, 10-48 weeks). Duration of
treatment with thalidomide ranged from 1 up to 40 weeks, with a median
of 7 weeks (Table 2). In 7 patients,
thalidomide administration had to be stopped within the first month
because of early disease progression and death (3 patients), personal
decision (2 patients), or drug intolerance (2 patients) on the lowest
dose level of 200 mg/d. Of the 3 patients who had progressive disease
and died, 2 showed a white blood cell count of
21.4 × 109/L (21 400/µL) and
27 × 109/L (27 000/µL), respectively, before
the start of treatment. The remaining 13 patients were treated for more
than 4 weeks with thalidomide after achieving the maximal tolerable
dose of 200 to 400 mg/d.
No patient tolerated a thalidomide dose above 400 mg daily without adverse events of grade 2 or more according to the classification system of the World Health Organization (Table 2). Especially, fatigue up to grade 2 (12 patients) and constipation up to grade 3 (9 patients) despite the use of laxatives required dose reduction. Five patients developed rashes after the second week of thalidomide administration. As additional side effect, peripheral neuropathy of grade 2 with tremor as the main symptom, occurred in 4 patients and resulted in withdrawal from the study in 2 of the patients on the lowest dose level. After dose reduction or discontinuation, symptoms of neuropathy completely resolved. Of the 13 patients receiving thalidomide for longer than 4 weeks, 4 patients achieved PR and 1 patient achieved HI (Table 2). Three of
these 5 patients had de novo AML; 2, secondary AML. Cytogenetic
analyses, available in 4 of the responding patients, revealed an
unfavorable karyotype in 1 patient, del(7)(q31), t(1;7)(q11;q22), and
normal karyotypes in the 3 other patients. Four of the responding patients had received prior chemotherapy regimens (1 patient had had 1 regimen; 3 patients, 2 or more regimens). Two patients were in first, 1 patient in second AML relapse; 1 patient was refractory to previous
chemotherapy; 1 patient was untreated. The other 8 patients had
progressive disease after 4 weeks of thalidomide and were taken off the
study. In all 5 responding patients (4 PRs, 1 HI), a significant
increase in the platelet counts was observed when median values of the
period before (day
In the 2 previously anemic patients, the hemoglobin concentrations increased independently from red blood cell (RBC) transfusions or erythropoietin administration (Figure 1B). In patient no. 1, this increase was sustained until day +282, reaching a maximum hemoglobin value of 144 g/L (14.4 g/dL) on day +205 of thalidomide treatment. However, median hemoglobin values of the entire group obtained in the period from 20 days before thalidomide treatment until treatment were not significantly different from those obtained during (day +1 to +45) thalidomide treatment (P = .893, Wilcoxon test; Figure 1B). The absolute neutrophil counts remained unchanged (data not shown). The median treatment duration was 7 weeks (range, 1-40 weeks), and the duration of the response lasted a median of 3 months (range, 1-8 months). There was no relationship between thalidomide dose and response (P = .49 for the comparison of thalidomide dose between responders and nonresponders; Fisher exact test). Parallel to the decrease of the leukemic blast cell infiltration in the
bone marrow of responding patients, a significant drop of the
microvessel counts was observed after 1 month of thalidomide treatment
(P < .05, Wilcoxon test; Figure
2). Figure
3 illustrates the significant decrease
in microvessel density after 1 month of treatment with thalidomide in a
patient who achieved a PR (patient no. 11). In contrast, the
progression of the leukemic blast cell infiltration in the bone marrow
of nonresponding patients was associated with a significant increase in
the bone marrow microvessel density (P < .05, Wilcoxon
test; Figure 2). Apart from intraindividual differences, the responding
patients revealed significantly lower microvessel densities after
thalidomide administration than nonresponders (median [LQ-HQ] 18.5 [18.3-19.3] versus 26.1 [25.9-29.4]/ × 500 field;
P = .014, Mann-Whitney rank sum test for independent
groups), whereas there was no difference in marrow vascularity before
treatment (P = .24). Nevertheless, microvessel counts in
the responding patients did not reach the normal range of the
previously described control group of 22 patients (median [LQ-HQ]
13.2 [11.4-14.8]/ × 500 field;
P = .001).2
VEGF and bFGF plasma levels of the entire patient population were
within the normal range of the controls. After 1 month of treatment
with thalidomide, VEGF plasma levels decreased in 3 of 5 responding
patients, whereas an increase was observed in 5 of 6 nonresponders
(P = .197 for the comparison of change in VEGF between
responders and nonresponders, Fisher exact test; Figure
4A). A similar pattern was observed for
the bFGF plasma levels, with a drop in all responding patients
and an increase in 4 of 6 nonresponders (P = .045 for the
comparison of change in bFGF between responders and nonresponders,
Fisher exact test; Figure 4B).
In the search for novel therapeutic targets for AML, angiogenesis seems to be a promising candidate, given the observation of increased microvessel density in AML2,17,18 and the growing biologic data that demonstrate overexpression of inducers of angiogenesis such as VEGF and bFGF.17-22 This phase I/II dose-escalating study of thalidomide is the first prospective trial of an antiangiogenic agent in a small group of patients with AML, most of whom had proved to be refractory toward intensive cytotoxic chemotherapy. The results demonstrate that thalidomide has antileukemic activity in this patient population, with 4 patients achieving PR and 1 patient achieving HI (response rate, 25%; 95% confidence intervals, 8.6%-49.1%). In the responding patients, platelet counts significantly increased, demonstrating a biologically relevant effect of thalidomide. In contrast, although the hemoglobin concentration increased in the 2 previously anemic patients, this did not reach statistical significance for the entire group. This observation is most likely due to the fact that the change in hemoglobin concentrations is underestimated because anemic patients had received RBC transfusions in the period before thalidomide administration. No complete or partial remissions according to consensus definitions were observed.14,23 However, this was not unexpected given the fact that most of the patients had relapsed/refractory AML. The exact mechanism of the antileukemic activity of thalidomide remains to be elucidated. The significant decrease in the microvessel density in responding patients in contrast to the nonresponders is consistent with the hypothesis that the observed antileukemic activity might have been mediated through an antiangiogenesis mechanism. This would be in line with recent reports of the antiangiogenic activity of thalidomide in animal models4,5 and its direct inhibitory effect on endothelial proliferation.6 However, it is also possible that the apparent antileukemic effects of thalidomide may not be solely attributable to antiangiogenesis, but rather were mediated directly through other mechanisms, such as the demonstrated ability of thalidomide to induce oxidative damage to DNA mediated by free radicals.24 Thus, the observed decrease in microvessel density in responding patients may be in part indirectly mediated by a loss of survival signals from leukemic blasts undergoing apoptosis, since a decrease in microvessel density has also been noted after administration of cytotoxic chemotherapy.2 Furthermore, the ability of thalidomide to modulate the immune system25-31 or to alter the profile of adhesion molecules32 may contribute to its antileukemic effects. Of course, antiangiogenic and antileukemic activities of thalidomide could enhance each other, since paracrine growth signal exchange between AML blasts and endothelial cells has been proposed.19,22 To gain further insight into the mechanism of thalidomide activity, we studied circulating markers of angiogenesis. There was a significant relationship between the decrease in bFGF plasma levels and response to thalidomide treatment. Whether bFGF is directly down-regulated by thalidomide, or whether the decrease merely reflects an antileukemic effect of treatment, remains to be elucidated. In contrast, we did not observe a consistent effect on VEGF levels in responding patients. This might be due to interindividual variation and/or the small number of patients studied. The profile of side effects observed in this trial is less favorable than that observed in previous studies in solid tumors and AIDS-related Kaposi sarcoma.7,9,10 According to the strict criteria of the study protocol, no patient tolerated thalidomide doses above 400 mg daily without adverse events of grade 2 or higher. Factors contributing to the higher observed incidence of toxicities, especially fatigue, constipation, and neuropathy, may be the advanced age, the anemia, and the pretreatment with intensive cytotoxic chemotherapy of our patient population. However, it has to be emphasized that 13 of 20 patients did stay on treatment for a median of 9 weeks (range, 5-40 weeks). Therefore, thalidomide should be explored earlier in the course of the disease, and other antiangiogenic drugs or analogs of thalidomide with fewer side effects are needed. We did not observe any relationship between dose of thalidomide and response. This might be due to the low variation in the final dose of thalidomide because we considered grade 2 toxicities to be dose limiting in order not to further compromise quality of life with this investigational therapy. Thus, we cannot exclude the possibility that higher doses of thalidomide have greater efficacy. On the other hand, the nature of the dose-response curve for thalidomide is not well characterized in either AML or other hematologic11 or nonhematologic malignancies.7-9 Therefore, dose escalation to the maximum tolerable dose may or may not be the most appropriate dose-finding strategy. This has to be addressed in future studies. Since thalidomide has only modest activity as a single agent, its future role in the treatment of AML has to be determined. There are growing data demonstrating synergism between antiangiogenic agents and traditional cytotoxic therapies.33-35 Therefore, it might be promising to include thalidomide in standard induction chemotherapy regimens. A recent abstract report on a study randomizing patients with newly diagnosed AML or myelodysplastic syndrome with excessive blasts and abnormal karyotypes, except inv(16), t(8;21), and t(15;17) to liposomal daunorubicin plus ara-C with or without thalidomide showed no difference in early CR rates in the 2 arms.36 However, early CR rate may not be the appropriate clinical end point for an antiangiogenic agent, because antiangiogenic treatment strategies might have higher efficacy in a state of minimal residual disease. Therefore, evaluation of thalidomide or other more selective antiangiogenic agents as maintenance therapy may be more promising. In summary, thalidomide has antiangiogenic and antileukemic activity in AML. Thus, thalidomide and more specific antiangiogenic principles should be further evaluated in clinical trials for the treatment of AML.
The authors are indebted to Achim Heinecke, PhD, of the Department of Biostatistics, University of Muenster, Germany, for his biostatistical advice and assistance.
Submitted April 10, 2001; accepted September 26, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Rolf M. Mesters or Wolfgang E. Berdel, Dept of Medicine/Hematology and Oncology, University of Muenster, Albert-Schweitzer-Strasse 33, D-48129 Muenster, Germany; e-mail: mesters{at}uni-muenster.de.
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© 2002 by The American Society of Hematology.
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Top
Abstract
Introduction
, patient no. 1; 
, patient no. 3; 
,
patient no. 5; 
, patient no. 11; 
, patient no. 20). Closed
symbols denote the values obtained on the day when thalidomide was
started (day 0). (A) Median platelet counts were significantly higher
during thalidomide treatment (day +1 to +45) compared with the
pretreatment period (day 
