Introduction
Myelodysplastic syndrome (MDS) is a heterogeneous
clonal haematopoietic stem cell disorder characterised by
ineffective haematopoiesis and a high risk of progression to acute
myeloid leukemia (AML). The ineffective haematopoiesis results in
one or more peripheral cytopaenias, dysplasic changes in the
haematopoietic cell lines and typical cytogenetic abnormalities
(1). Conventional drugs, including
haematopoietic cytokines and chemotherapy drugs, have shown little
efficacy in the treatment of the disease, although in recent years,
numerous new drugs have been listed or have been subject to
clinical trials. Three drugs have recently been approved by the US
Food and Drug Administration (FDA) for the treatment of MDS within
the last seven years: lenalidomide, azacytidine and decitabine.
Lenalidomide is predominantly used for the treatment of patients
with MDS with 5q deletion [del (5q)] cytogenetic abnormalities.
However, the 2009 version of the National Comprehensive Cancer
Network (NCCN) guidelines also recommended lenalidomide for the
management of low/intermediate-1 risk MDS.
A number of studies have demonstrated that
lenalidomide treatment is effective in patients with MDS with del
(5q), and may increase the number of peripheral blood cells, thus
enabling patients to undergo a reduced number of infusions, and
improving the quality of life (2–4).
However, there have been few investigations into the efficacy of
lenalidomide for patients with intermediate-1 risk MDS without del
(5q), particularly amongst Chinese individuals. Since March 2009,
the treatment of patients with low/intermediate-1 risk MDS at the
Department of Haematology and Oncology of The First Hospital of
Jilin University (Changchun, China) has included the administration
of lenalidomide. By March 2011, 30 patients had received this
treatment. The clinical data obtained from the patients are
summarised in the current study.
Patients and methods
Patients
A total of 30 patients in the Department of
Haematology and Oncology of The First Hospital of Jilin University
were diagnosed with MDS through peripheral blood counts, bone
marrow smears, bone marrow biopsies and cytogenetic analyses. This
study was conducted in accordance with the Declaration of Helsinki
and with approval from the Ethics Committee of the First Hospital
of Jilin University. Written informed consent was obtained from all
participants. All patients were classified through G-banding
chromosome karyotype analysis combined with a fluorescence in
situ hybridization (FISH) test (+8, −5/5q-, −7/7q-, 20q-, −Y
and −12/12p- were selected as the cytogenetic probes in the FISH
method). Karyotype anomalies were found in 11 cases, including
seven with 20q-, three with +8, one with dup (1) (q22 31), and four cases that failed in
the karyotype analysis. The FISH test revealed anomalies in 17
cases, including six with +8, seven with 20q-, four with 12p- and
13 cases with negative results. The patients included 14 males and
16 females, with ages ranging from 13 to 83 years old (median age,
52 years). The duration between diagnosis and treatment ranged from
0 to 9 months (mean, 4.1 months). Six cases of refractory anemia
(RA), one case of refractory thrombocytopaenia (RT), one case of
refractory anemia with ring sideroblasts (RARS), 17 cases of
refractory cytopaenia with multilineage dysplasia (RCMD) and five
cases of MDS-unclassified (MDS-U) were identified according to the
World Health Organization (WHO) classification system (5). In addition, the International
Prognostic Scoring System (IPSS) was used evaluate the 30 patients,
and of these, 23 had a score of 0.5 and seven had a score of 1.0
(5). The average erythropoietin
(EPO) levels were >500 mU/ml in all the patients; in addition,
two out of 27 cases tested positive for human leukocyte antigen
(HLA)-DR15.
Management
Lenalidomide (Revlimid®, 10 mg/day) was
administered for 21 days every 28 days. All 30 cases were treated
with at least three cycles, with 20 cases being treated with four
cycles. Red blood cell transfusion was given to those with
symptomatic anaemia, and platelet transfusions were given to those
with platelet counts of <6×109/l or those with
obvious thrombocytopenic bleeding. None of the patients required
EPO, cyclosporine (CSA) or iron chelation treatments.
Evaluation
Peripheral blood cell counts were monitored every
3–5 days, whereas liver and renal functions were reviewed every two
weeks. The bone marrow morphology, cytogenetic analysis and FISH
test were performed once the patients had undergone three cycles of
treatment.
Statistical analysis
Statistical data were processed using SPSS
statistical software version 13.0 (SPSS, Inc., Chicago, IL, USA),
and comparisons among groups were conducted using a t-test.
P<0.05 was considered to indicate a statistically significant
result.
Results
Changes in peripheral blood cell counts
in the 30 patients following treatment
The efficacy of lenalidomide as a treatment for
patients with intermediate-1 risk non-del (5q) MDS was demonstrated
by the peripheral blood cell counts of the patients showing
improvement following lenalidomide treatment. A total of 2–4 cycles
of treatment resulted in the absolute neutrophil, haemoglobin and
platelet counts of the patients increasing; however, the changes
were not statistically significant (P>0.05). Analysis within the
subgroups showed that the differences in the peripheral blood cell
counts between the patients with scores of 0.5 and a duration of ≤3
months between diagnosis and treatment and the patients with scores
of 1.0 and a duration of >3 months between diagnosis and
treatment were statistically significant (P<0.05). Platelet
recovery in the former subgroup was more rapid and marked, with the
fastest platelet recovery of 20q- observed in seven patients.
However, patients with initial platelet counts of
<10×109/l and haemoglobin levels of <45 g/l
demonstrated a poor response to the treatment (Tables II and III, respectively).
 | Table IIChanges in peripheral blood cell
counts following treatment (n=30). |
Table II
Changes in peripheral blood cell
counts following treatment (n=30).
| | Following
treatment |
|---|
| |
|
|---|
| Peripheral blood
cell counts | Prior to
treatment | 2 cycles | 4 cycles |
|---|
| Absolute neutrophil
count (×109/l) | 0.95±0.47 | 1.02±0.59 | 1.28±0.84 |
| Haemoglobin
(g/l) | 59.1±16.1 | 61.6±16.8 | 68.6±14.8 |
| Platelet count
(×109/l) | 30.7±67.8 | 40.2±18.8 | 50.1±85.6 |
| Table IIIChanges in platelet count following
treatment in the subgroups. |
Table III
Changes in platelet count following
treatment in the subgroups.
| Subgroup | n | Count prior to
treatment (×109/l) | Count following 3
cycles (×109/l) | P-value |
|---|
| Time from diagnosis
to treatment ≤3 months; IPSS=0.5 | 14 | 31.4±29.6 | 58.6±25.8 | <0.05 |
| Time from diagnosis
to treatment >3 months; IPSS=1.0 | 16 | 26.5±48.6 | 31.7±68.3 | >0.05 |
Evaluation of the bone marrow morphology
and cytogenetic analysis
All patients became stable following three cycles of
treatment; however, 17 cases with chromosomal abnormalities
demonstrated no cytogenetic response, as confirmed by the FISH
test.
Adverse events
In the first two weeks, 40% of the patients treated
with lenalidomide exhibited mild rashes (12 cases); however, the
majority of them recovered without any treatment. One case was
treated with glucocorticoids and an HT-3 receptor antagonist.
Within one week, 11 patients (36.67%) who had initially shown
abdominal distension experienced an improvement in the symptoms
with continuous lenalidomide treatment. Following three cycles of
treatment, one patient suffered from deep venous thrombosis (DVT)
in the left lower limb, and although urokinase was administered,
the thrombosis was not completely recanalised. In addition, all
patients presented with liver and kidney dysfunctions.
Discussion
Lenalidomide exhibits immunological and biological
properties, extending to cytokine modulation, T-cell costimulation
and angiogenesis inhibition (6–8).
Therefore, the effects of the drug on the MDS clone and the
microenvironment may contribute to the therapeutic action. These
effects include, but are not limited to, suppression of tumor
necrosis factor-α and the induction of other inflammatory
cytokines, such as interleukins-1β, 6, 8 and 12; costimulation of
the T-cell-specific immune response; expansion of natural killer
cells and enhancement of cytotoxicity; suppression of the
endothelial response to angiogenic molecules; downregulation of
cell-adhesion molecules; potentiation of EPO-receptor signaling and
modification of lineage commitment. Furthermore, lenalidomide has
been demonstrated to promote cell cycle arrest and display direct
antineoplastic activity in a variety of cancer cell lines and
primary specimens. Although a precise cellular target has not been
identified to date, recent investigations have indicated that
lenalidomide acts through the inhibition of phosphatase activity in
the common deleted region (CDR) of 5q, which is important in cell
cycle regulation through a defect in ribosomal protein function. As
such, lenalidomide acts through direct cytotoxic mechanisms in
patients with the del (5q) cytogenetic abnormality, in addition to
affecting the bone marrow microenvironment in patients without this
lesion (by suppressing the effects of proapoptotic and
proinflammatory cytokines) (4,9–11).
The beneficial results of lenalidomide have been
particularly evident for patients with del (5q) chromosome
abnormalities (10,12,13).
A randomised clinical trial demonstrated that lenalidomide
treatment may have been effective in improving the health-related
quality of life (HRQL) outcomes of the tested patients (14). Lenalidomide has recently been
approved by the FDA for the treatment of patients with low-risk
MDS, particularly for patients with del (5q)(15). For patients without del (5q),
however, the effects of lenalidomide remain unclear, and its
potential use and activity in non-del (5q) MDS require further
investigation (16,17). A phase II study evaluated
lenalidomide efficacy in 214 transfusion-dependent patients with
low or intermediate-1 risk MDS without del (5q). The results showed
that 26% of the non-del (5q) patients achieved transfusion
independence following a median of 4.8 weeks of treatment (13). In a study by Sibon et
al(18), 31 consecutive
patients with lower-risk non-del (5q) MDS and anemia refractory to
erythropoiesis-stimulating agents (ESA) were treated with
lenalidomide in a compassionate programme. A total of 15 patients
(48%) demonstrated an erythroid response, including 10 of the 27
(37%) previously transfusion-dependent (RBC-TD) patients who became
transfusion-independent (RBC-TI). Out of these 15 patients, nine
experienced a relapse, while the remaining six (40%) were still
responding and transfusion-free for at least 11(+)–31(+) months
subsequently (median time, 24 months). There was a lower erythroid
response rate in patients with refractory cytopaenia with
multilineage dysplasia (27% versus 60%); in addition, the response
rate tended to be higher in patients treated with lenalidomide in
combination with ESA (55% versus 36%). The response duration was
significantly longer in patients who became RBC-TI and in patients
treated with lenalidomide following primary resistance to ESA. It
was concluded that lenalidomide was an interesting second-line
therapeutic option and that the combination of lenalidomide with
ESAs in the context of the study required further investigation
(18).
The present study aimed to observe the efficacy of
lenalidomide in patients with intermediate-1 risk non-del (5q) MDS.
It was observed that lenalidomide did not result in complete
haematological remission in the patients, although it improved the
peripheral blood cell counts in the patients with intermediate-1
risk MDS. Platelet recovery was more marked in the patients with
IPSS scores of 0.5 and with a duration of ≤3 months between
diagnosis and treatment. The majority of patients achieved platelet
transfusion independence, i.e. the safety level of non-spontaneous
bleeding (≥20×109/l). Furthermore, certain patients
achieved red blood cell transfusion independence (≥60 g/l)
following treatment. Patients with initial platelet and haemoglobin
counts of <10×109/l and <45 g/l, respectively,
demonstrated a poor response to the treatment. Patients with a
duration of <3 months between diagnosis and treatment showed
marked improvements in their blood cell counts, whereas those with
a duration of >3 months between diagnosis and treatment
demonstrated no apparent improvement. Therefore, lenalidomide is
not a recommended treatment for patients with severe cytopaenia and
with a prolonged duration between diagnosis and treatment.
At present, two phase III studies on lenalidomide
are underway. One of these is known as the AZA-004 trial, which
studies the effect of lenalidomide on the transformation of MDS
into AML (19). The other study is
examining the efficacy of lenalidomide in patients with non-del
(5q) intermediate-1 risk MDS. It is expected that satisfactory
results will be obtained from these two clinical trials.
The reported rate of DVT (VTE) for patients with MDS
receiving lenalidomide during the first 2 years of post-marketing
exposure has been revealed to be low (0.53%). Disproportionality
analysis demonstrated a statistically meaningful correlation
between VTE and lenalidomide concomitantly used with ESAs in
patients with MDS; however, the correlation was not statistically
significant when lenalidomide was used in the absence of ESAs
(20). Of the 30 patients examined
in the current study, one patient suffered from DVT in the left
lower limb following three cycles of treatment, and although
urokinase was administered, the thrombosis was not completely
recanalised. This result was not consistent with those presented in
other studies, and more cases are required to make further
observations.
In conclusion, lenalidomide has demonstrated
efficacy in patients with intermediate-1 risk non-del (5q) MDS, and
is indicated to be a safe form of treatment.
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