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      Long-term hematological response in a patient with 5q- syndrome after suspension of lenalidomide therapy and further improvement with deferasirox therapy

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          Abstract

          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.

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          International scoring system for evaluating prognosis in myelodysplastic syndromes.

          Despite multiple disparate prognostic risk analysis systems for evaluating clinical outcome for patients with myelodysplastic syndrome (MDS), imprecision persists with such analyses. To attempt to improve on these systems, an International MDS Risk Analysis Workshop combined cytogenetic, morphological, and clinical data from seven large previously reported risk-based studies that had generated prognostic systems. A global analysis was performed on these patients, and critical prognostic variables were re-evaluated to generate a consensus prognostic system, particularly using a more refined bone marrow (BM) cytogenetic classification. Univariate analysis indicated that the major variables having an impact on disease outcome for evolution to acute myeloid leukemia were cytogenetic abnormalities, percentage of BM myeloblasts, and number of cytopenias; for survival, in addition to the above, variables also included age and gender. Cytogenetic subgroups of outcome were as follows: "good" outcomes were normal, -Y alone, del(5q) alone, del(20q) alone; "poor" outcomes were complex (ie, > or = 3 abnormalities) or chromosome 7 anomalies; and "intermediate" outcomes were other abnormalities. Multivariate analysis combined these cytogenetic subgroups with percentage of BM blasts and number of cytopenias to generate a prognostic model. Weighting these variables by their statistical power separated patients into distinctive subgroups of risk for 25% of patients to undergo evolution to acute myeloid leukemia, with: low (31% of patients), 9.4 years; intermediate-1 (INT-1; 39%), 3.3 years; INT-2 (22%), 1.1 years; and high (8%), 0.2 year. These features also separated patients into similar distinctive risk groups for median survival: low, 5.7 years; INT-1, 3.5 years; INT-2, 1.2 years; and high, 0.4 year. Stratification for age further improved analysis of survival. Compared with prior risk-based classifications, this International Prognostic Scoring System provides an improved method for evaluating prognosis in MDS. This classification system should prove useful for more precise design and analysis of therapeutic trials in this disease.
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            Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes.

            The aims of this study were to identify the most significant prognostic factors in myelodysplastic syndromes (MDS) taking into account both their values at clinical onset and their changes in time and to develop a dynamic model for predicting survival and leukemic evolution that can be applied at any time during the course of the disease. We studied a learning cohort of 426 MDS patients diagnosed at the Department of Hematology, San Matteo Hospital, Pavia, Italy, between 1992 and 2004, and a validation cohort of 739 patients diagnosed at the Heinrich-Heine-University Hospital, Düsseldorf, Germany, between 1982 and 2003. All patients were reclassified according to WHO criteria. Univariable and multivariable analyses were performed using Cox models with time-dependent covariates. The most important variables for the prognostic model were WHO subgroups, karyotype, and transfusion requirement. We defined a WHO classification-based prognostic scoring system (WPSS) that was able to classify patients into five risk groups showing different survivals (median survival from 12 to 103 months) and probabilities of leukemic evolution (P < .001). WPSS was shown to predict survival and leukemia progression at any time during follow-up (P < .001), and its prognostic value was confirmed in the validation cohort. WPSS is a dynamic prognostic scoring system that provides an accurate prediction of survival and risk of leukemic evolution in MDS patients at any time during the course of their disease. This time-dependent system seems particularly useful in lower risk patients and may be used for implementing risk-adapted treatment strategies.
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              Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes.

              Reductions in transfusion requirements/improvements in hematologic parameters have been associated with iron chelation therapy in transfusion-dependent patients, including those with myelodysplastic syndromes; data on there reductions/improvements have been limited to case reports and small studies. To explore this observation in a large population of patients, we report a post-hoc analysis evaluating hematologic response to deferasirox in a cohort of iron-overloaded patients with myelodysplastic syndromes enrolled in the Evaluation of Patients' Iron Chelation with Exjade(®) (EPIC) study using International Working Group 2006 criteria. Two-hundred and forty-seven, 100 and 50 patients without concomitant medication for myelodysplastic syndromes were eligible for analysis of erythroid, platelet and neutrophil responses, respectively. Erythroid, platelet and neutrophil responses were observed in 21.5% (53/247), 13.0% (13/100) and 22.0% (11/50) of the patients after a median of 109, 169 and 226 days, respectively. Median serum ferritin reductions were greater in hematologic responders compared with non-responders at end of study, although these differences were not statistically significant. A reduction in labile plasma iron to less than 0.4 μmol/L was observed from week 12 onwards; this change did not differ between hematologic responders and non-responders. This analysis suggests that deferasirox treatment for up to 1 year could lead to improvement in hematologic parameters in some patients with myelodysplastic syndromes.
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                Author and article information

                Journal
                Blood Res
                Blood Res
                BR
                Blood research
                Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis
                2287-979X
                2288-0011
                June 2014
                25 June 2014
                : 49
                : 2
                : 130-137
                Affiliations
                [1 ]Hematology Unit, S. Eugenio Hospital, Rome, Italy.
                [2 ]Department of Clinical Pathology (Cytogenetic Unit), Regina Elena Cancer Institute, Rome, Italy.
                Author notes
                Correspondence to: Pasquale Niscola. Hematology Unit, Piazzale dell'Umanesimo 10, 00144 Rome, Italy. pniscola@ 123456gmail.com
                Article
                10.5045/br.2014.49.2.130
                4090335
                c6bca8a3-f729-49eb-a58b-83b4257e5261
                © 2014 Korean Society of Hematology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 05 February 2014
                : 12 March 2014
                : 15 May 2014
                Categories
                Letter to the Editor

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