Thalidomide for the treatment of myelodysplastic syndrome in Taiwan: results of a phase II trial.
ABSTRACT Thalidomide inhibits angiogenesis and exerts complex immunomodulatory activities. This phase II study aimed to examine the efficacy of thalidomide in Taiwanese patients with myelodysplastic syndrome (MDS).
Sixty patients [intention to treat group (ITT)] with MDS were treated with thalidomide (100 mg/day, increased by 100 mg/day weekly to a maximum of 400 mg/day) for 12 weeks. Forty-two patients of the ITT group were considered as comprising the evaluable population (EP).
Thalidomide resulted in hematological improvement (HI) in 28% of ITT analysis and in HI in 40% of the EP. Thalidomide was more effective for MDS patients with low to intermediate-1 International Prognostic Score System scores. The response rates were 7% for ITT and 10% for EP patients. Only two patients exhibited a cytogenetic response. Net reduced levels of vascular endothelial growth factor and basic fibroblast growth factor cytokines were observed in the peripheral blood and the bone marrow of thalidomide-treated patients.
Low-dose thalidomide is an effective and safe treatment for patients with low-risk MDS.
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ABSTRACT: The extensive autoimmune, anti-inflammatory, and anticancer applications of thalidomide have inspired a growing number of studies and clinical trials. As an inexpensive agent with relatively low toxicity, thalidomide is regarded as a promising therapeutic candidate, especially for malignant diseases. We review its therapeutic effects in hematology, including those on multiple myeloma, Waldenstroem macroglobulinemia, lymphoma, mantle-cell lymphoma, myelodysplastic syndrome, hereditary hemorrhagic telangiectasia, and graft-versus-host disease. Most studies have shown satisfactory results, although several have reported the opposite. Aside from optimal outcomes, the toxicities and adverse effects of thalidomide should also be examined. The current work includes a discussion of the mechanisms through which the novel biological effects of thalidomide occur, although more studies should be devoted to this aspect. With appropriate safeguards, thalidomide may benefit patients suffering from a broad variety of disorders, particularly refractory and resistant diseases.Frontiers of medicine. 07/2013;
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ABSTRACT: Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) are frequently associated with clinical manifestations of autoimmune disorders (AD) and inflammatory response of the immune system. AD accompanying MDS and CMML include vasculitis, seronegative polyarthritis and neutrophilic dermatosis. Rare AD including relapsing polychondritis is strongly associated with MDS as in a high proportion of those patients MDS is diagnosed during disease course. Antinuclear antibodies (ANA) are frequently found among MDS patients without clinical manifestation of AD. In a subset of patients, MDS and resulting cytopenias appear to be the consequence of auto reactive immunologic activity and may respond to immunosuppressive treatment (IST). Increased release of inflammatory cytokines like tumor necrosis factor-(TNF)-α and interferon (IF)-γ triggers apoptosis of myeloid precursor cells leading to cytopenias. Impaired function of immune cells including cytotoxic, regulatory (Treg), helper (Th17) T cells and NK cells also appears to predict response to IST, outcome and occurrence of AD.Best practice & research. Clinical haematology 12/2013; 26(4):327-336. · 3.13 Impact Factor
Abstract. Background: Thalidomide inhibits angiogenesis
and exerts complex immunomodulatory activities. This phase
II study aimed to examine the efficacy of thalidomide in
Taiwanese patients with myelodysplastic syndrome (MDS).
Patients and Methods: Sixty patients [intention to treat group
(ITT)] with MDS were treated with thalidomide (100 mg/day,
increased by 100 mg/day weekly to a maximum of
400 mg/day) for 12 weeks. Forty-two patients of the ITT
group were considered as comprising the evaluable
population (EP). Results: Thalidomide resulted in
hematological improvement (HI) in 28% of ITT analysis and
in HI in 40% of the EP. Thalidomide was more effective for
MDS patients with low to intermediate-1 International
Prognostic Score System scores. The response rates were 7%
for ITT and 10% for EP patients. Only two patients exhibited
a cytogenetic response. Net reduced levels of vascular
endothelial growth factor and basic fibroblast growth factor
cytokines were observed in the peripheral blood and the bone
marrow of thalidomide-treated patients. Conclusion: Low-
dose thalidomide is an effective and safe treatment for
patients with low-risk MDS.
The myelodysplastic syndromes (MDS) are a heterogeneous
collection of hematological disorders characterized in most
patients by cytopenia as the result of progressive bone
marrow failure (1). MDS is regarded as a preleukemic
disorder from which a substantial proportion of patients
progress to acute myeloid leukemia (AML). Bone marrow
transplantation is the only treatment for MDS that has the
potential to induce long-term remission; allogeneic stem cell
transplantation and chemotherapy have been shown to
improve survival in some patients (2, 3). However, the
treatment goal in the majority of patients with MDS remains
palliation, in which the increase in quality of life and
reduction in the likelihood of progression to AML are the
pharmacological and immunological effects, such as down-
regulation of tumor necrosis factors alpha (TNF-α) (4, 5),
up-regulation of adhesion molecules (6), and inhibition of
angiogenesis (7). Treatment with thalidomide has been
shown to improve anemia and long-term survival for
patients with MDS (8-14). We conducted a single-arm,
multicenter, open label, phase II clinical study of
thalidomide for Taiwanese patients with MDS. The
primary endpoint was to determine the hematological
improvement (HI). Secondary endpoints of the study
included determining the response to and the toxicity of
thalidomide in these patients. Other hematological and
immunological features that may indicate sensitivity to
thalidomide, including levels of TNF-α, interferon gamma
(IFN-γ), interleukin-6 (IL-6), vascular endothelial growth
factor (VEGF), and those of basic fibroblast growth factor
(bFGF) in the peripheral blood and bone marrow of
patients with MDS were also investigated.
exerts a broad spectrum of
Correspondence to: Cheng-Shyong Chang, MD, Division of
Hematology and Oncology, Department of Internal Medicine,
Changhua Christian Hospital, 135 Nanhsiao Street, Changhua
County 500, Taiwan, R.O.C. Tel: +886 47238595 ext. 1940, Fax:
+886 47200931, e-mail: email@example.com or Tzeon-Jye Chiou,
MD, Division of Transfusion Medicine, Department of Medicine,
Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road,
Taipei 11217, Taiwan, R.O.C. e-mail: firstname.lastname@example.org
Key Words: Thalidomide, myelodysplastic syndromes, angiogenesis,
ANTICANCER RESEARCH 32: 3415-3420 (2012)
Thalidomide for the Treatment of Myelodysplastic
Syndrome in Taiwan: Results of a Phase II Trial
CHIH-YUAN CHUNG1, SHENG-FUNG LIN2, PO-MIN CHEN3, MING-CHIH CHANG4,
WOEI-YOU KAO5, TSU-YI CHAO5, LIANG-TSAI HSIAO3, CHUEN-CHUAN YEN3, MUH-HWA YANG3,
WEI-SHOU HWANG6, TUNG-LIANG LIN7, TZEON-JYE CHIOU3and CHENG-SHYONG CHANG1
1Department of Internal Medicine, Changhua Christian Hospital, Taiwan, R.O.C.;
2Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, R.O.C.;
3Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.;
4Department of Internal Medicine, Mackey Memorial Hospital, Taipei, Taiwan, R.O.C.;
5Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan, R.O.C.;
6Department of Internal Medicine, Chi Mei Foundation Hospital, Tainan, Taiwan, R.O.C.;
7Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.
Patients and Methods
Eligibility criteria. This phase II, single-arm, non-comparative, and
open label clinical trial was conducted across seven centers in
Taiwan between September 2004 and November 2007. Inclusion
criteria were diagnosis of MDS of the following subtypes according
to the French-American-British criteria: Refractory anemia (RA),
RA with ringed sideroblasts (RARS), chronic myelomonocytic
leukemia (CMML), and refractory anemia with excess blasts
(RAEB). Patients were required to meet one of the following
hematological criteria: i). Pre-transfusion hemoglobin ≤10 g/dl; ii).
pre-transfusion platelet count ≤50,000/mm3; iii). absolute neutrophil
count ≤1,000/mm3. None of the patients had received any therapy
for MDS for at least 30 days prior to the study, with the exception
of supportive care with transfusions. Patients with a diagnosis of
malignant condition or infection were excluded, as were patients
who had undergone previous thalidomide treatment. This protocol
was approved by the local Ethic Review Boards, and written
informed consent was obtained from all patients.
The primary endpoint was HI. HI included erythroid response
(HI-E), platelet response (HI-P), and neutrophil response (HI-N). A
major HI-E was defined as an increase in hemoglobin (Hb) greater
than 2 g/dl for patients with Hb <11 g/dl, and as transfusion
independence for patients who were transfusion-dependent prior to
treatment; a minor HI-E was defined as an increase of 1 to 2 g/dl
in Hb for patients with pre-treatment Hb <11 g/dl, and as a 50%
decrease in packed red blood cell requirement for transfusion-
dependent patients. A major HI-P was defined as an absolute
increase of >30,000/μl for patients with a platelet count
<100,000/μl, and as stabilization of platelet count and platelet
transfusion independence for platelet transfusion-dependent patients;
a minor HI-P was defined as a 50%, or greater increase in platelet
count with a net increase greater than 10,000/μl but less than
30,000/μl, for patients with a pre-treatment platelet count less than
100,000/μl. For HI-N, a greater than 100% increase or an absolute
increase of greater than 500/μl, whichever was greater, for patients
with an absolute neutrophil lower than 1500/μl before therapy, was
defined as a major response; a minor response was defined as an
absolute neutrophil increase of at least 100% but an absolute
increase of less than 500/μl.
The secondary objectives of the study included the response rate
and the toxicity of this regimen in these patients. The response rate
was defined as the sum of the proportions of patients graded as
having complete remission (CR) or partial remission (PR).
Moreover, cytogenetic response and changes in the levels of TNF-α,
IFN-γ, IL-6, VEGF, and bFGF in the peripheral blood and bone
marrow were assessed in these patients.
Treatment. Patients received 50 mg of thalidomide orally twice daily
during the study period. The dose of thalidomide was escalated
weekly by 100 mg/day, if no grade 3 non-hematological toxicity
occurred, until the dose reached 400 mg/day. All eligible patients
were enrolled into the thalidomide treatment group. Patients were
on thalidomide for 12 weeks and were followed-up for treatment
response every 4 weeks for up to 16 weeks. The two study
populations were the intention-to-treat (ITT) population and the
evaluable population (EP). The ITT group was defined as those
patients who were exposed to at least one study regimen. The EP
was the subset of the ITT patients who completed baseline
evaluation and had at least one post-treatment evaluation.
Overall, 43 (71.7%) male and 17 (28.3%) female patients were
enrolled in this study. The demographic characteristics of the
60 MDS patients are summarized in Table I. The duration of
MDS was defined as the time between the day of diagnosis of
MDS and the first day the study drug was given. The average
duration of MDS was 132.87±385.78 days. In terms of MDS
types, 24 patients (40.0%) had RA, 3 patients (5.0%) had
RARS, and 33 patients (55.0%) had RAEB. The majority
(91.7%) of patients had pre-transfusion hemoglobin ≤10 g/dl
(Table II). Treatment duration and the mean daily dose of
thalidomide are summarized in Table III. The mean treatment
duration was 105.73±69.22 days and the mean daily dose was
204.52±84.13 mg/day (Table III).
HI response. Overall, 17 (28%) out of the 60 patients of the
ITT group achieved an HI, 6 (10%) achieved major HI and
11 (18%) achieved minor HI (Table IV). Stratifying patients
by International Prognostic Score System (IPSS) into risk
groups indicated that most HI responders were patients with
low or intermediate-1 risk MDS (Table V).
Response rate and cytogenetic response. Four patients (6.7%
of the ITT group or 9.5% of the EP) exhibited complete
remission (CR) or partial remission (PR). From the
cytogenetic point of view, only one patient (1.7% of the ITT
group or 2.4% of EP) had a major response and one patient
(1.7% of the ITT group or 2.4% of EP) a minor response
ANTICANCER RESEARCH 32: 3415-3420 (2012)
Table I. Summary of patients’ demographics and characteristics.
Demographic characteristic Total (N=60)
SD: Standard deviation; IQR: interquartile range, BMI: body mass
Cytokine changes. The effect of thalidomide on the
concentration of several cytokines, and on angiogenic and
growth factors including TNF-α, IFN- γ, IL-6, VEGF, and
bFGF were measured. The net change between week 12, the
last study treatment visit, and the baseline of the investigated
cytokines are listed in Table VII. Net reduced levels of TNF-
α, VEGF and bFGF cytokine were observed in the peripheral
blood of patients treated with thalidomide. Similarly, reductions
of VEGF and bFGF were also noted in the bone marrow.
Adverse events. Adverse events (AEs) were measured using
The Coding Symbols for a Thesaurus of Adverse Reaction
Terms (15). A total of 910 AEs were reported, out of which
58.0% were grade 1, followed by 25.5%, 12.6%, 3.3%, and
0.2% of grade 2, 3, 4, and grade 5 AEs, respectively. Out of
the 910 AEs reported, 189 (20.8%) were marked as being
treatment related. The most frequent reported treatment-related
AEs occurring in the ITT population was constipation
(85.0%), followed by leukopenia (50.0%) and dizziness
(41.7%). Table VIII summarizes adverse events with an
incidence greater than 30%.
Thalidomide has demonstrated anti-inflammatory, immuno-
modulatory, and antiangiogenic effects in vitro (16, 17).
Thalidomide disturbs angiogenesis mediated by bFGF and
VEGF, inhibits TNF-α gene activation by reducing nuclear
factor kappa-light-chain-enhancer of activated B cells
binding, and reduces IL-6 secretion (18-21). These
antiangiogenic, immunomodulatory, and growth-suppressive
effects form the rationale for investigating thalidomide in the
treatment of various types of malignancy. The heterogeneous
biological effects of thalidomide on hematopoiesis have
supported its use in the treatment of MDS (8-14).
This single-arm, non-comparative, multicenter, and open
label phase II clinical trial aimed to examine the efficacy of
thalidomide in patients with MDS in Taiwan. The primary
endpoint of the trial was HI which included HI-E, HI-P, and
HI-N. Administration of thalidomide, increasing from 100 mg
Chung et al: Thalidomide for Myelodysplastic Syndrome
Table II. Disease evaluation of patients with myelodysplastic syndrome (MDS) at baseline.
Baseline characteristicTotal (N=60)
Duration of MDS (days)Mean (SD)
Pre-transfusion Hb ≤10 g/dl
Pre-transfusion platelets ≤50,000/mm3
Absolute neutrophils ≤1,000/mm3
33 ( 55.0%)
Type of MDS
ECOG performance at screening visit
SD: Standard deviation; IQR: interquartile range; RA: refractory anemia; RARS: RA with ringed sideroblasts; RAEB: refractory anemia with excess
blasts; ECOG: Eastern Cooperative Oncology Group.
Table III. Thalidomide treatment duration and the mean daily dose.
Treatment duration (days) Mean (SD)
Mean daily dose1(mg/day)
SD: Standard deviation; 1mean daily dose=dose actually taken (mg)/
duration of exposure (day).
Table IV. Hematological improvement in the ITT population.
Hematological improvement (HI)ResponseN (%)
HI-E: Erythroid response; HI-P: platelet response; HI-N: neutrophil
per day to no more than 400 mg per day over 12 weeks,
resulted in HI in 28% of patients in the ITT analysis and in
40% in the EP. As indicated by HI, thalidomide provided
more effective results for patients with MDS with a low to
intermediate-1 IPSS score. These treatment response results
obtained from patients with MDS in Taiwan fall within
previous findings by other groups (11, 22, 23).
The secondary endpoints of the study were to determine
the response to and toxicity of thalidomide in these patients.
The response rate that indicated the proportion of patients
having CR or PR was 6.7% in the ITT population and 9.5%
in the EP. Only two patients exhibited a cytogenetic response
to thalidomide treatment. The second aim of our study also
included monitoring of the impact of thalidomide on several
factors implicated in angiogenesis and immunomodulation in
patients with MDS. Levels of TNF-α, VEGF and bFGF were
reduced in the peripheral blood and reduction of VEGF and
bFGF were noted in the bone marrow of patients. Given the
wide ranges in the levels of these cytokines in this small
sample, the correlation between these changes and the
clinical benefit from treatment with thalidomide could not be
established in this study.
In general, the safety profile of thalidomide in this study
was within what we expected from the studied regimen and
correlated with what has been reported previously (11, 22,
23). In the absence of serious side-effects, a low thalidomide
dose of 100 mg/day, with an increase, if tolerated, to 400 mg,
may produce favorable responses in patients with MDS.
ANTICANCER RESEARCH 32: 3415-3420 (2012)
Table V. Hematological improvement (HI) in the intent to treat (ITT)
group and evaluable population (EP) by International Prognostic Score
System (IPSS) scores.
ITTLow Intermediate-1 Intermediate-2High Total
14 30151 60
EP LowIntermediate-1Intermediate-2 High Total
9 2580 42
Table VI. Treatment and cytogenetic response.
Category N (%) 95% CI
ITT: Intent to treat; EP: evaluable population; CI: confidence interval.
Table VIII. Adverse events with incidence greater than 30% in 60
patients with myelodysplastic syndrome.
Table VII. Net change from baseline to the end of treatment of
concentrations of the investigated cytokines.
TNF-α: Tumor necrosis factors alpha; IFN-γ: interferon gamma; IL-6:
interleukin-6; VEGF: vascular endothelial growth factor; bFGF: basic
fibroblast growth factor.
In summary, this clinical study showed that thalidomide was
efficacious and improved hematopoiesis in at least a subset of
patients with MDS. Patients with a low to intermediate-1 IPSS
score were most likely to respond. Future clinical studies
should be designed in order to confirm the angiogenic and
immunomodulatory properties of thalidomide in larger sample
sizes and to examine the efficacy of combining thalidomide
with other therapies to further improve treatment response.
Declaration of interests
The Authors have declared that no competing interest exists.
We thank Wei-Shu Wang, Ta-Chung Chao, Po Dunn, Po-Nan Wang,
Jin-Hou Wu, Ming-Chung Kuo, Hung Chang, Chung-Chih Tang,
Chao-Jung Tsao, Tsai-Yun Chen, Jih-Luh Tang, Ruey-Kuen Hsieh,
Johnson Lin, Yi-Fang Chang, Gung-Shen Chen, and the Clinical Trials
Committee of the Hematology Society of Taiwan for their assistance in
this trial. This work was supported by TTY Biopharm Co., Ltd.
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analogs: pomalidomide and lenalidomide,
Received March 26, 2012
Revised May 9, 2012
Accepted May 11, 2012
Chung et al: Thalidomide for Myelodysplastic Syndrome