TO THE EDITOR: Anemia and its related clinical effects, including dependence on red
blood cells (RBC) transfusions, are common findings in patients affected by myelodysplastic
syndromes (MDS) with isolated chromosome 5q deletion (5q-). However, in recent years,
the use of lenalidomide in the management of anemia related to 5q- syndrome has significantly
changed the clinical scenario in this specific setting [1]. Several reports have described
durable erythroid responses and the achievement of transfusion independence in patients
with 5q- syndrome who were treated with lenalidomide despite the discontinuation of
this agent and the persistence of the underlying malignant clone [1, 2, 3, 4]. In
addition, both anemia and transfusion are paradoxically associated with organ injury
[5], for which iron chelation therapy (ICT) plays an expanding role in the global
management of transfusion-dependent patients with MDS. ICT with deferasirox has been
associated with hematological improvement and achievement of transfusion independence
in some patients with MDS [6, 7], and a potential synergistic effect between deferasirox
and lenalidomide has been suggested [4]. Here we describe the unusual outcome of a
patient with 5q- syndrome who experienced an early and long-lasting response to lenalidomide
despite discontinuation of therapy; interestingly, the hematological and cytogenetic
responses improved during treatment with deferasirox, which was given as a single
agent on a long-term basis after the suspension of lenalidomide therapy.
Using the International Prognostic Scoring System [8], low-risk MDS typical of 5q-
syndrome was diagnosed in a 69-year-old woman in July 2007. Apart from well-controlled
arterial hypertension and mild kidney failure, the patient's previous pathological
history was unremarkable. Complete blood cell count revealed severe macrocytic anemia
(hemoglobin [Hb] level, 66 g/L; mean corpuscular volume, 121 fL; reticulocyte count,
0.2%) and thrombocytosis (platelet count, 681×109/L). Total and differential white
blood cells (WBC) counts were within normal limits. All possible pathologies potentially
mimicking this framework were ruled out. In particular, JAK2 V617F mutation analysis
was negative, and hepatic diseases, hypovitaminosis, and hemolytic disorders were
excluded. The common parameters regarding iron metabolism were within normal limits;
the baseline serum ferritin level was 137 mg/L. Examination of bone marrow (BM) showed
prominent erythroid dysplasia and an increased number of hypolobular megakaryocytes
without blasts. Cytogenetic analysis revealed isolated del [(5)(q13q33)] in 20 of
20 (100%) analyzed metaphases. The patient initially received packed RBC transfusions
and soon after was started on erythropoietin stimulation; however, the latter treatment
allowed for only a transient and partial response. After about 6 months, the patient's
anemia worsened and she became severely transfusion dependent, regularly needing about
2 units of RBCs every 2 to 3 weeks, so treatment with erythropoietin was discontinued.
The patient began treatment with deferasirox in 2010 at an adjusted starting dose
of 10 mg/kg and reached a maximum daily dose of 20 mg/kg because of her slightly reduced
renal function (creatinine clearance, 60 mL/min); at that time, her serum ferritin
level was 1,857 ng/mL. However, her compliance with treatment was low, and treatment
was often discontinued. In addition, the patient was reluctant to initiate treatment
with lenalidomide, which was repeatedly proposed. However, because of the increasing
need for transfusions and the appearance of both neutropenia (neutrophil count, 0.5×109/L)
and thrombocytopenia (platelet count, 83×109/L), the patient was reevaluated in August
2012. A comprehensive hematological workup showed 5% of myeloblasts in the BM; the
same karyotype was confirmed by cytogenetic analysis, ruling out additional chromosomal
abnormalities. At the time of reassessment, the patient had received 118 RBC units
and her serum ferritin level was 2,100 ng/mL; her International Prognostic Scoring
System and World Health Organization Classification-Based Prognostic Scoring System
[9] scores were 1 (intermediate-1 risk) and 3 (high risk), respectively. After a frank
discussion with the patient and her family regarding the need to adhere to proper
treatment because of disease progression, the patient began treatment with lenalidomide
(5 mg orally on days 1??1 of repeated 28-day cycles) at an adjusted starting dose
because of her renal impairment [10] and concomitant treatment with deferasirox (20
mg/kg/day). Treatment with low-dose acetylsalicylic acid was also initiated for secondary
antithrombotic prevention. The patient was more motivated than in 2010, resulting
in good compliance with therapy. The hematological response was immediate, and no
further transfusions have been required since the initiation of lenalidomide therapy.
However, after the fourth cycle of lenalidomide therapy, an excessive erythroid response
was observed; the patient's Hb values ranged from 14 to 16 g/dL without any clinical
complications. Improvements in platelet and neutrophil counts were also observed.
BM examination revealed full clearance of myeloblasts but the persistence of prominent
erythroid dysplasia and an increased number of hypolobular megakaryocytes, although
the latter was not increased; cytogenetic analysis showed 10 of 20 (50%) 5q- metaphases.
Given the excessively high Hb levels, lenalidomide therapy was suspended and the patient
continued treatment with deferasirox alone in January 2013. Treatment was well tolerated;
except for 2 episodes of severe but uncomplicated neutropenia, the patient did not
experience any adverse effects. In particular, renal function was preserved and no
signs of renal tubulopathy or decreased creatinine clearance were recorded.
As of December 2013, 12 months after the discontinuation of lenalidomide therapy,
the patient is well and has achieved near normalization of her hemogram (Hb, 13.1
g/L; mean corpuscular volume, 107 fL; reticulocyte count, 4%; platelet count, 182×109/L;
normal total and differential WBC counts). Her last serum ferritin level was 482 ng/mL.
Moreover, compared with previous BM examinations, a significantly less prominent erythrodysplasia
and a reduced number of altered megakaryocytes were observed. In addition, no blasts
were found. Cytogenetic analysis revealed the persistence of isolated 5q- alteration
in 6 of 20 (30%) BM metaphases. The patient is regularly followed up and continues
treatment with deferasirox alone at a reduced dose.
We have reported a case of long-term disease control in a patient with 5q- syndrome
after suspension of lenalidomide therapy despite the persistence of the abnormal clone;
at the same time, the patient's clinical course and hematological findings suggest
that iron overload may have exerted a role in the progression of MDS. In this case,
iron chelation therapy may have led to the improvement of erythroid dysplasia and
the reduction of the cytogenetically abnormal clone that we observed during prolonged
treatment with deferasirox by antioxidative mechanisms due to iron chelation itself
and perhaps by other biological effects exerted by this agent. However, this case
has only anecdotal value, and our interpretations of this unusual outcome are purely
hypothetical and unproven by biological studies. Despite these limitations, we suggest
that treatment with lenalidomide plus deferasirox should be explored in appropriately
designated clinical trials in the setting of transfusion-dependent MDS.