• clinical trials;
  • hematologic diseases;
  • International Prognostic Scoring System;
  • leukemia;
  • myelodysplastic syndromes;
  • thalidomide


  1. Top of page
  2. Abstract
  6. Acknowledgements


Thalidomide has shown promise for the treatment of patients with myelodysplastic syndrome. The current prospective multicenter study examined the efficacy and toxicity of thalidomide in adult patients with myelodysplastic syndrome.


Using the International Prognostic Scoring System (IPSS), patients were stratified into 2 groups: favorable (IPSS score, 0–1.0) or unfavorable (IPSS score, 1.5–3.5). Seventy-two patients (42 of whom were favorable and 30 of whom were unfavorable) received a starting dose of oral thalidomide of 200 mg daily. The dose was increased by 50 mg per week to a targeted maximum daily dose of 1000 mg.


According to the International Working Group response criteria for myelodysplastic syndrome, 1 patient in the unfavorable group achieved a partial remission with a complete cytogenetic response. Overall, 2 patients (5%) in the favorable group and 4 patients (14%) in the unfavorable group experienced either a hematologic improvement or a partial response. The most frequent Grade 3 or 4 (grading was based on the National Cancer Institute's Common Toxicity Criteria [version 2.0]) nonhematologic adverse events were fatigue (24%), infection (19%), neuropathy (13%), dyspnea (8%), and constipation (7%).


Thalidomide alone, at the schedule and dose levels used in the current study, is not a safe and viable therapeutic option for patients with myelodysplastic syndrome. Limited efficacy and increased toxicity were observed in the current Phase II trial. Cancer 2006. © 2006 American Cancer Society.

The myelodysplastic syndromes (MDS) are a heterogeneous and relatively common group of clonal hematologic disorders characterized by varying degrees of peripheral blood cytopenias and bone marrow dyshematopoiesis.1, 2

The specific pathogenesis of MDS is unknown. As many as 50% to 80% of MDS patients have cytogenetic abnormalities, which indicates that these disorders may represent a clonal evolution from a marrow stem cell with an acquired genetic mutation.3, 4 Abnormally elevated concentrations of cytokines have been found in the bone marrow and plasma of MDS patients. Specific cytokines that have been pathogenetically implicated include tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), and interleukin 1-β (IL-1β).5–11 These cytokines, by promoting the apoptosis of intramedullary hematopoietic cells, may be responsible in part for the paradox between the marrow hypercellularity and peripheral blood cytopenias observed in MDS patients. Evidence has also emerged of an immune-mediated suppression of hematopoiesis in MDS patients. Clonality or oligoclonality of T cells has been observed in MDS,12–15 and T cells isolated from the bone marrow of MDS patients have been found to inhibit granulopoiesis and erythropoiesis.16–18 Increased bone marrow neovascularization has been associated with various hematologic malignancies, including MDS, and this phenomenon may contribute to the perpetuation of the abnormal clone in these disorders.19–23

Thalidomide, a derivative of glutamic acid, selectively inhibits the production of TNF-α. Thalidomide also inhibits the in vitro production of other cytokines, such as TGF-β and IL-1β.24–27 In addition, it inhibits angiogenesis and has been found to decrease the helper to suppressor T-cell ratio in the peripheral blood of healthy men.28, 29 Because this pharmacologic agent can potentially target several abnormal pathways involved in the pathogenesis of MDS, we elected to proceed with this Phase II trial.


  1. Top of page
  2. Abstract
  6. Acknowledgements

This study was approved by the Mayo Foundation Institutional Review Board and signed informed consent was obtained from all patients. All prescribing physicians and patients were required to comply with the manufacturer's System for Thalidomide Education and Prescription Safety program. The study was sponsored by the National Cancer Institute's Cancer Therapy Evaluation Program (NCI-CTEP), which provided the study medication free of charge to participants. The study was limited to adult patients (age >18 years) with any subtype of MDS, advanced disease (defined as having a pretransfusion hemoglobin value of ≤10 g/dL, a platelet count of ≤50 × 109/L, or a baseline absolute neutrophil count of <1 × 109/L), and preserved renal and liver function; however, no limitations were set for performance status. All patients were assigned a score based on the International Prognostic Scoring System (IPSS).30 The efficacy analysis was based on response criteria for MDS established by the International Working Group.31 In this single-stage Phase II study, the primary end point for each prognostic group was a confirmed response rate or hematologic improvement on 2 consecutive evaluations at least 8 weeks apart. Toxicity grading was based on the National Cancer Institute's Common Toxicity Criteria (version 2.0). A minimum of 10 and a maximum of 29 evaluable patients was to be accrued to each group unless undue toxicity was encountered. We anticipated accruing an additional 3 patients to each group in order to account for ineligibility, cancellation, major treatment violations, or other reasons. The largest success proportion for which the proposed treatment regimen would be considered ineffective in this population was 5%, and the smallest success proportion that would warrant subsequent studies with the proposed regimen in this patient population was 20%.

Bone marrow analysis of potential participants was obtained within 30 days before they entered the study and at Weeks 12 and 24 after initiation of treatment if the patients were still receiving thalidomide. All bone marrow samples were submitted to the North Central Cancer Treatment Group (NCCTG) and reviewed by the same panel of experienced central hematopathologists at Mayo. Because the trial was initially designed in early 1998 and based on the initial trials with thalidomide for multiple myeloma, the NCCTG decided to test a similar dose regimen in patients with MDS. All patients received a single nighttime oral dose starting at 200 mg daily. The dose was increased weekly by 50 mg to a target daily dose of 1000 mg. When toxicity was encountered the dose was decreased by 50% to alleviate side effects, then slowly titrated to the upper limit of tolerability. Any patient unable to tolerate the medication after it was decreased to the minimum dose of 50 mg per day was removed from the study. A cycle was defined as 4 weeks (28 days).

Adverse events (AEs) were defined as all events observed during this trial. The definition of toxicity was limited to side effects attributable to thalidomide. The overall response of patients as well as any toxicities and adverse events were summarized using frequency and descriptive techniques to assess patterns. Ninety-five percent confidence intervals (95% CIs) were calculated using exact binomial 95% CIs. The Kaplan–Meier method32 was used to analyze overall survival, progression-free survival, and time to discontinuation of treatment.


  1. Top of page
  2. Abstract
  6. Acknowledgements

Between April 2001 and February 2002, 73 patients were accrued, stratified into 2 groups on the basis of their IPSS scores, and prospectively followed. These 2 groups included 43 patients in the favorable group (IPSS score, 0–1.0) and 30 patients in the unfavorable group (IPSS score, 1.5–3.5). After central pathologic review, 4 patients (3 in the favorable group and 1 in the unfavorable group) were deemed ineligible because they did not appear to have MDS. A fifth patient (favorable group) decided to leave the study before receiving any treatment. These 5 patients were excluded from the efficacy analysis, but the 4 ineligible patients who received thalidomide during the course of the study were included in the tolerability assessment.

The pretreatment characteristics of all eligible patients are summarized in Table 1. Both groups had a preponderance of men, and most patients were age ≥60 years. Thirty-four (87%) of 39 patients in the favorable group and 19 (66%) of 29 patients in the unfavorable group were dependent on erythrocyte or platelet transfusions before entering the study. By the former French-American-British classification system and the new MDS classification system of the World Health Organization (WHO),33, 34 20 patients (51%) in the favorable group had a diagnosis of refractory anemia with ringed sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia (RCMD), and 24 patients (83%) in the unfavorable group carried a diagnosis of refractory anemia with excess blasts (RAEB) or of refractory anemia with excess blasts in transformation (RAEB-t).

Table 1. Characteristics of Patients with Myelodysplastic Syndrome Treated with Thalidomide
Characteristic, no.Prognosis
Favorable (n = 39)Unfavorable (n = 29)
  1. MDS indicates myelodysplastic syndrome; WHO, World Health Organization; FAB, French-American-British classification; RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; CMML, chronic myelomonocytic leukemia; RAEB, refractory anemia with excess blasts; RAEB-t, refractory anemia with excess blasts in transformation; RCMD, refractory cytopenias with multilineage dysplasia; IPSS, International Prognostic Scoring System; NA, not applicable; INT-1, intermediate 1; INT-2, intermediate 2.

Age group
 <60 y42
 ≥60 y3527
Age, y
 Median (range)73 (51–88)71 (57–89)
Transfusion-dependency (red blood cells and/or platelets) within 3 months of study entry3419
Bone marrow cytogenetics
 Not performed10
Bone marrow blasts, %
MDS subtype (WHO/FAB)
 5q– syndrome20
IPSS score
 0.0 (low)13NA
 0.5–1.0 (INT-1)26NA
 1.5–2.0 (INT-2)NA22
 2.5–3.5 (high)NA7

Thalidomide Treatment Efficacy

By the response criteria of the International Working Group, only 2 patients (5%; 95% CI, 0%–17%) in the favorable group responded to the study medication (Table 2). Both patients achieved minor hematologic improvement in red blood cells because of a decrease in transfusion requirements from 2 units of packed red blood cells every 2 weeks to 2 units every 8 weeks in 1 patient and from 1 unit per week to 1 unit every other week in the other patient. In the unfavorable group, 4 (14%) of 29 patients (95% CI, 0–32%) had a hematologic response. These 4 responses included 1 partial hematologic remission with associated complete cytogenetic remission, 1 major erythroid response, 1 major platelet response, and 1 minor red blood cell response (Table 2). Initial hematologic improvement for these 6 patients was noted at a median of 6 weeks (range, 4–16 weeks). All these responses were confirmed at subsequent evaluations.

Table 2. Efficacy of Thalidomide for Myelodysplastic Syndrome by Type of Response*
Favorable (n = 39)Unfavorable (n = 29)
  • *

    According to criteria of the International Working Group.31

Complete remission00
Partial remission01
Hematologic improvement
Stable disease3016
Failure or transformation79

Of the 6 patients who responded, 5 carried a diagnosis of RAEB and all 6 of them belonged to the intermediate-risk 1 and 2 categories on the basis of their IPSS scores (Table 3). Two of the responders had a del(20)(q13.1) cytogenetic abnormality, 1 had an abnormality of chromosome 7 (−7), and 1 had combined abnormalities of chromosomes 7 and del(20) (q11.1; q13.1). Of the other 2 patients, 1 had a deletion of chromosome 1 and 1 had normal cytogenetics.

Table 3. Response to Thalidomide by Prognostic Score, Bone Marrow Blasts, Karyotype, and WHO/FAB Criteria
ResponseIPSS scoreBMB, %KaryotypeWHO/FAB criteria
  1. WHO indicates World Health Organization; FAB, French-American-British classification system; IPSS, International Prognostic Scoring System; BMB, bone marrow blasts; RAEB, refractory anemia with excess blasts; RCMD, refractory cytopenia with multilineage dysplasia.

Favorable group
 Minor hematologic improvement (n = 2)
 Unfavorable group
 Partial remission (n = 1)1.5145,XX,–7[6]/46,XX[24]RCMD
 Major hematologic improvement (n = 2)
 Minor hematologic improvement (n = 1)
 Erythroid2.0646,XY,der(7)t(1;7)(q21;q11.2)[2]/46, XY,der(7)t(1;7)(q21;q11.2),del(20) (q11.1;q13.1)[16]/46,XY[2]RAEB

Forty-six (68%) of the 62 nonresponding patients in the 2 groups (n = 68) were classified as achieving, at best, stabilization of disease. A total of 16 patients (24%) in the 2 groups (n = 68) had treatment that was classified as a failure because they died while in the study or their disease progressed to more advanced MDS or acute myeloid leukemia (AML) (Table 2).

Thalidomide Drug Tolerability

All 72 patients who received thalidomide during the course of the study were included for drug tolerability and toxicity analysis (Table 4). All patients have discontinued therapy with thalidomide. The median number of cycles received was 3 (1–15 cycles for the favorable group and 1–18 cycles for the unfavorable group). Only 53% of all patients were able to receive 3 or more cycles of thalidomide therapy. The median maximum daily dose of thalidomide tolerated by the patients in the study was 300 mg (range, 200–1000 mg per day; 200–300 mg for 38 patients, 350–450 mg for 18, 500–600 mg for 7, and 650–1000 mg for 5). Twenty-two patients (52%) in the favorable group of 42 patients and 17 patients (57%) in the unfavorable group of 30 patients discontinued treatment either because of adverse drug reactions or refusal for other reasons (e.g., worsening fatigue, neuropathy, generalized weakness, or a feeling of a worsening quality of life without a corresponding hematologic improvement). However, approximately one-third of the patients in each group discontinued therapy because of disease progression or the transformation of their MDS into AML.

Table 4. Reasons for Discontinuing Thalidomide Treatment
Favorable (n = 42)Unfavorable (n = 30)
Disease progression1511
Adverse reactions1414
Refused further treatment63
Other medical problems20
Died during study21
New primary disease10

Thalidomide Drug Toxicity

A major difficulty in this study was the significant incidence of AEs encountered by patients. Approximately 62% of all patients had Grade 3 or 4 nonhematologic AEs. The most frequent were fatigue (24%), infection (19%), neuropathy (13%), dyspnea (8%), and constipation (7%). Three patients sustained Grade 5 AEs: myocardial infarction, pneumonia associated with a rapid progression of MDS into AML, and hemorrhage. However, in only 1 case was the event attributed to thalidomide toxicity. More than 90% of those in each group had Grade 3 or 4 hematologic AEs. The most common hematologic AEs were a decrease in hematocrit or platelet count or the need for transfusions. For most patients with severe peripheral blood cytopenias caused by MDS, treatment-related hematologic toxicity was difficult to assess. Thalidomide-attributed nonhematologic toxicity of Grade 3 or higher occurred in 48% of patients in the favorable group and in 53% of patients in the unfavorable group. The most common nonhematologic toxicities were fatigue, neuropathy, and constipation. The 2 prognostic groups had no significant difference in the incidence of severe nonhematologic AEs or toxicity.

Survival and Progression

At a median follow-up of 23 months (range, 16–31 months), 19 (28%) of the 68 patients were still alive. The estimated median survival of patients in the favorable group was 17 months (95% CI, 14–25 months), which was significantly longer (P = .004) than the 8-month median survival of patients in the unfavorable group (95% CI, 4–13 months). In the favorable group, 32 (82%) of the 39 patients experienced disease progression compared with 27 (93%) of 29 patients in the unfavorable group. The estimated median time to progression was 3 months for both groups, with a 95% CI of 3 months to 8 months for patients in the favorable group and 2.5 months to 3.8 months for those in the unfavorable group (P = .09).


  1. Top of page
  2. Abstract
  6. Acknowledgements

MDS is a common hematologic disorder in the elderly. The initial study of thalidomide therapy for MDS by Raza et al.33 reported that 16 (19%) of 83 patients had some hematologic improvement, including 10 who no longer required transfusions of red blood cells. The median time to response was 16 weeks (range, 12–20 weeks). In their treatment trial, the planned maximum dose of thalidomide was 400 mg daily, but only 51 (61%) patients were able to complete at least 12 weeks of therapy. The main reasons for discontinuation of therapy were progression to leukemia, worsening medical problems, and intolerable side effects. The authors concluded that maintaining the dose of thalidomide at the maximally tolerated dose (150–200 mg/day) for as long as 6 months was important to achieve a favorable response.

In the current study, the planned maximum thalidomide dose was higher (1000 mg/day vs. 400 mg/day) but the side effects attributed to thalidomide were fairly similar in both trials. However, our study had a higher incidence of Grade 3 or Grade 4 nonhematologic toxicity. Regardless, our study clearly demonstrates that elderly MDS patients may not be able to tolerate a dose of more than 200-mg thalidomide daily.

Lenalidomide, a thalidomide analog with better tolerability and a lower toxicity profile than the parent drug, has shown encouraging results in patients with MDS, especially for those with MDS and cytogenetic analysis showing deletion of chromosome 5. The pivotal study by List et al.34 reported a 56% overall response rate to lenalidomide in adult patients with MDS. In our trial, 13 patients were identified as having a 5q– abnormality. Nine of these patients had single abnormalities, and in the other 4 the 5q– was part of complex cytogenetics. None of these patients achieved a meaningful response. However, of the 6 responders in our study, 3 had deletion 20q and 2 others had abnormalities involving chromosome 7.

The combined overall response rate in our trial was only 9% (6 of 68 patients; 95% CI, 3–18%). Our findings demonstrate very limited activity of thalidomide in unselected patients with MDS by using the dose and schedule of this study. Whether a lower thalidomide dose for a longer time would yield a higher response rate with a lower side effect profile is not known. However, on the basis of the results of this study, we are unable to recommend the current dosing schedule of thalidomide as a safe and viable therapeutic option for patients with MDS. Because MDS has a complex pathophysiology, multiple molecular pathways might have to be targeted simultaneously to achieve an effective treatment that radically alters the natural history of this disease.


  1. Top of page
  2. Abstract
  6. Acknowledgements

The study was conducted as a trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by the National Cancer Institute Department of Health and Human Services (Public Health Service grants CA-25224, CA-37404, CA-15083, CA-63826, CA-35431, and CA-60276).


  1. Top of page
  2. Abstract
  6. Acknowledgements