Clinical Management of Myelodysplastic Syndromes With Interstitial Deletion of Chromosome 5q

2006 ◽  
Vol 24 (16) ◽  
pp. 2576-2582 ◽  
Author(s):  
Stephen D. Nimer
Keyword(s):  
Myelodysplastic Syndromes ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Normal Karyotype ◽  
Transfusion Independence ◽  
Chromosome 5Q ◽  
Transfusion Requirements ◽  
Definition Of ◽  
Classification And Treatment ◽  
Rbc Transfusion

Deletions of the long (q) arm of chromosome 5 [del(5q)]occur in patients with myelodysplastic syndromes (MDS) including, but not limited to, those who meet the WHO definition of the 5q− syndrome. Del(5q) MDS patients frequently have symptomatic anemia, and its treatment has traditionally consisted of RBC transfusions and, for some, iron chelation therapy. Erythropoietin, darbepoetin, hypomethylating agents, and lenalidomide can enhance erythropoiesis in MDS patients with anemia, increasing hemoglobin levels and abrogating RBC transfusion requirements. Lenalidomide is particularly active in treating the anemia of del(5q) MDS, which is especially relevant given the low response rate to erythropoietin in this group of patients. In a recent study of 43 MDS patients, 10 of 12 patients (83%) with del(5q) MDS achieved sustained RBC transfusion independence (or a > 2 g/dL increase in hemoglobin), compared with 57% of those with a normal karyotype and 12% of those with other karyotypic abnormalities. Complete cytogenetic remissions were achieved in 75% (nine of 12) of the del(5q) MDS patients, suggesting that lenalidomide targets a fundamental pathogenetic feature of MDS that is more pronounced in the presence of chromosomal 5q deletions. This review highlights some issues about the classification and treatment of del(5q) MDS.

scholarly journals Red Blood Cell Transfusion Independence Following the Initiation of Iron Chelation Therapy in Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4844-4844
Author(s):  
Maha A Badawi ◽  
Linda M Vickars ◽  
Jocelyn M Chase ◽  
Heather A Leitch
Keyword(s):  
Platelet Count ◽  
Myelodysplastic Syndrome ◽  
Research Funding ◽  
Chelation Therapy ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Transfusion Independence ◽  
Transfusion Requirements ◽  
Rbc Transfusion

Abstract Abstract 4844 Background Iron chelation therapy (ICT) is often used to treat iron overload (IOL) in patients (pts) requiring transfusion of red blood cells (RBC) for chronic anemia. In myelodysplastic syndrome (MDS), guidelines recommend consideration of ICT in pts with lower risk International Prognostic Scoring System (IPSS) and IOL as defined by a ferritin level >1000 ug/l; IOL related organ dysfunction; or receipt of ≥20 RBC units. During treatment of a pt with MDS and IOL with ICT, RBC transfusion requirement (TR) ceased. Here we report his course and review reported cases of RBC transfusion independence (TI) or decreased RBC TR in MDS pts receiving ICT. Methods The pt chart was reviewed and reported cases identified by PubMed search using the terms ‘MDS’ and ‘iron chelation’. The clinical characteristics and course of published cases were summarized. Case A 76 year (y) old man was referred in May 2004 for management of MDS diagnosed in 1997, when the white blood cell (WBC) count was 2.4 ×109/l; neutrophils, 0.7 ×109/l; hemoglobin (Hb), 133 g/l; platelets, 108 ×109/l. Bone marrow aspiration and biopsy showed refractory anemia (RA), karyotype analysis 46,X,-Y,+8, and the IPSS score was intermediate-1. The erythropoitin (epo) level was 148.3 mIU/ml and the stem cell assay showed no epo-independent colony growth. In 2004 the Hb dropped to 60 g/l prompting the initiation of RBC transfusion support. He required 3 RBC units every 4 weeks to maintain a Hb >90 g/l and complained of fatigue and functional limitation. Creatinine, bilirubin, TSH, reticulocyte count, B12 and folate levels were all normal. The ferritin level in 2004 was 1293 ug/l and 2197 ug/l in 2006. He declined ICT with deferoxamine (DFO) but in 2006 accepted deferasirox (DFX). He required several dose interruptions and adjustments for renal insufficiency; the current dose is 5mg/kg/d with a normal creatinine. Two months (mo) after starting ICT, the Hb increased spontaneously to 109 g/l and he has not required RBC transfusion since. The mean Hb since starting ICT was 122 g/l and the ferritin decreased to 1082 ug/l in 2009. The most recent neutrophil count was 3.5 ×109/l, platelets consistently clump and the MCV is unchanged at 120 fl. He reports excellent energy and an improved quality of life, and has remained clinically well and RBC transfusion independent to the present, 36 mo from the initiation of ICT. Literature review There are 18 published cases of MDS showing improvement in Hb with ICT; 9 became RBC transfusion independent. Characteristics of the 10 TI pts were: median age at MDS diagnosis 58 (range 18-74) y; male, n=5. MDS subtype: RA, n=5; RARS, n=2, RCMD, n=1; RAEB, n=2. IPSS (reported in 8): low, n=1; int-1, n=5; int-1 or 2, n=1; high, n=1. ICT was: DFO, n=7; DFX, n=3. Median time to RBC TI was 17.5 (1-24) mo and TI duration 13 (3-28) mo to date. Of pts who had decreased RBC transfusion requirements with ICT but did not achieve transfusion independence: median age (reported in 3) was 67 (45-78) y; gender (reported in 3) female, n=3; MDS subtype: RA, n=8; RAEB-t, n=1; IPSS: int-1, n=3; ICT: DFO, n=8; DFX, n=1. Median time to decreased TR was 14.4 (3-24) mo; median duration of decreased TR (reported in 3) 9 (6-32) mo; initial TR 50.9 (19.7-447) g Hb/mo; median decrease in TR 12.7 (0.1-88) g Hb/mo. In one report of 6 pts, 2 with pancytopenia showed improvement with ICT in WBC from 1.4 to 1.9 ×109/l (p<0.0001) and neutrophils from 0.51 to 0.94 ×109/l (p<0.001). The platelet count increased from 16.6 to 22.5 ×109/l (p<0.001) and 14.6 to 29.6 ×109/l (p<0.00001) within 3 mo and the MCV decreased significantly in 5 by a mean of 5.1 (2.1-11.7) fl, normalizing in 2. In a second report, neutrophils increased in 8 of 9 pts; in 4 the initial neutrophil count was <1 ×109/l, and platelet counts increased in 7 of 11 pts, in 4 the initial platelet count was <20 ×109/l. Conclusions In summary, our pt is the 19th patient with MDS reported to date in whom improved Hb followed the initiation of ICT; 9 had a decrease in RBC transfusion requirements, and RBC transfusion independence occurred in 10. The remarkable course of these pts adds to evidence that ICT may be of clinical benefit for selected patients with MDS and IOL. Although the improvement in WBC and platelet counts with ICT in some pts implies a suppressive effect of IOL on hematopoiesis that may be abrogated by ICT, the mechanism by which the effects of ICT on transfusion requirements occur, and the frequency with which they occur, remains an area for future investigation. Disclosures Off Label Use: This presentation discusses the use of iron chelation therapy deferoxamine and deferasirox in patients with myelodysplastic syndrome.. Vickars:Novartis Canada: Honoraria, Research Funding. Leitch:Novartis Canada: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Red Blood Cell Transfusion Independence Following the Initiation of Iron Chelation Therapy in Myelodysplastic Syndrome

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Maha A. Badawi ◽  
Linda M. Vickars ◽  
Jocelyn M. Chase ◽  
Heather A. Leitch
Keyword(s):  
Time Course ◽  
Chelation Therapy ◽  
Transfusion Requirement ◽  
Iron Chelation ◽  
Hemoglobin Level ◽  
Red Blood Cell Transfusion ◽  
Iron Chelation Therapy ◽  
Transfusion Independence ◽  
Transfusion Requirements ◽  
Rbc Transfusion

Iron chelation therapy is often used to treat iron overload in patients requiring transfusion of red blood cells (RBC). A 76-year-old man with MDS type refractory cytopenia with multilineage dysplasia, intermediate-1 IPSS risk, was referred when he became transfusion dependent. He declined infusional chelation but subsequently accepted oral therapy. Following the initiation of chelation, RBC transfusion requirement ceased and he remained transfusion independent over 40 months later. Over the same time course, ferritin levels decreased but did not normalize. There have been eighteen other MDS patients reported showing improvement in hemoglobin level with iron chelation; nine became transfusion independent, nine had decreased transfusion requirements, and some showed improved trilineage myelopoiesis. The clinical features of these patients are summarized and possible mechanisms for such an effect of iron chelation on cytopenias are discussed.

scholarly journals Durable Red Blood Cell Transfusion Independence in a Patient with an MDS/MPN Overlap Syndrome Following Discontinuation of Iron Chelation Therapy

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Harpreet Kochhar ◽  
Chantal S. Leger ◽  
Heather A. Leitch
Keyword(s):  
Blood Cell ◽  
Iron Overload ◽  
Red Blood Cell ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Red Blood Cell Transfusion ◽  
Favorable Effect ◽  
Iron Chelation Therapy ◽  
Transfusion Independence ◽  
Rbc Transfusion

Background. Hematologic improvement (HI) occurs in some patients with acquired anemias and transfusional iron overload receiving iron chelation therapy (ICT) but there is little information on transfusion status after stopping chelation.Case Report. A patient with low IPSS risk RARS-T evolved to myelofibrosis developed a regular red blood cell (RBC) transfusion requirement. There was no response to a six-month course of study medication or to erythropoietin for three months. At 27 months of transfusion dependence, she started deferasirox and within 6 weeks became RBC transfusion independent, with the hemoglobin normalizing by 10 weeks of chelation. After 12 months of chelation, deferasirox was stopped; she remains RBC transfusion independent with a normal hemoglobin 17 months later. We report the patient’s course in detail and review the literature on HI with chelation.Discussion. There are reports of transfusion independence with ICT, but that transfusion independence may be sustained long term after stopping chelation deserves emphasis. This observation suggests that reduction of iron overload may have a lasting favorable effect on bone marrow failure in at least some patients with acquired anemias.

Myelodysplastic Syndromes: Iron Overload Consequences and Current Chelating Therapies

2006 ◽  
Vol 4 (1) ◽  
pp. 91-96 ◽  
Author(s):  
Peter L. Greenberg
Keyword(s):  
Iron Overload ◽  
Myelodysplastic Syndromes ◽  
Chelation Therapy ◽  
Oxygen Free Radicals ◽  
Clinical Course ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Red Blood Cell Transfusion ◽  
Clinical Effects ◽  
Transfusion Independence

Chronic red blood cell transfusion support in patients with myelodysplastic syndromes (MDS) is often necessary but may cause hemosiderosis and its consequences. The pathophysiologic effects of iron overload relate to increased non-transferrin bound iron generating toxic oxygen free radicals. Studies in patients with MDS and thalassemia major have shown adverse clinical effects of chronic iron overload on cardiac function in patients who underwent polytransfusion. Iron chelation therapy in patients with thalassemia who were effectively chelated has prevented or partially reversed some of these consequences. A small group of patients with MDS who had undergone effective subcutaneous desferrioxamine (DFO) chelation for 1 to 4 years showed substantial hematologic improvements, including transfusion independence. However, because chronic lengthy subcutaneous infusions of DFO in elderly patients have logistic difficulties, this chelation therapy is generally instituted late in the clinical course. Two oral iron chelators, deferiprone (L1) and deferasirox (ICL670), provide potentially useful treatment for iron overload. This article reviews data indicating that both agents are relatively well tolerated, were at least as effective as DFO for decreasing iron burdens in comparative thalassemia trials, and (for deferiprone) were associated with improved cardiac outcomes. These outcomes could potentially alter the tissue siderosis-associated morbidity of patients with MDS, particularly those with pre-existing cardiac disease.

The Costs of Drugs Used to Treat Myelodysplastic Syndromes Following National Comprehensive Cancer Network Guidelines

2008 ◽  
Vol 6 (9) ◽  
pp. 942-953 ◽  
Author(s):  
Peter L. Greenberg ◽  
Leon E. Cosler ◽  
Salvatore A. Ferro ◽  
Gary H. Lyman
Keyword(s):  
National Comprehensive Cancer Network ◽  
Myelodysplastic Syndromes ◽  
Iron Chelation ◽  
International Prognostic Scoring System ◽  
Limited Attention ◽  
Recombinant Erythropoietin ◽  
Nccn Guidelines ◽  
Transfusion Requirements ◽  
Average Annual Cost ◽  
Cancer Network

Guidelines for management of patients with myelodysplastic syndromes (MDS) have been generated by the National Comprehensive Cancer Network (NCCN) Myelodysplastic Syndromes Panel. Because MDS is a heterogeneous spectrum of disorders, these patients have been categorized into prognostic subgroups, predominantly using the International Prognostic Scoring System (IPSS). Several drugs have been used to treat these patients, and their selection and sequential recommended use by the panel depend on disease characteristics and responses to treatment. Recombinant erythropoietin alfa and darbepoetin alfa have been the mainstay of therapy for treating anemia associated with MDS. The FDA has recently approved several other drugs for treating MDS, including azacytidine and decitabine for all stages of disease, lenalidomide for low-risk anemic patients with del(5q) chromosomal abnormality, and deferasirox for treating iron overload. For iron chelation, deferoxamine is also used occasionally. Treatment with immunosuppressive therapy (antithymocyte globulin and cyclosporin) has been therapeutically beneficial for a subset of younger patients with MDS. Because the financial cost of these therapies are substantial and have received only limited attention, this article evaluates the costs of specific drugs and their sequential use in the lower-risk IPSS (low and intermediate-1) subgroups based on the NCCN guidelines. Results estimate an average annual cost for potentially anemia-altering drugs of $63,577 per patient, ranging from $26,000 to $95,000, depending on the specific therapies. In patients for whom the therapies fail, annual costs for iron chelation plus red blood cell transfusions are estimated to average $41,412. The economic impact of drug therapy should be weighed against the patient's potential for improvement in clinical outcomes, quality of life, and transfusion requirements.

Transfusion Dependence in Patients with Primary Myelofibrosis Has a Negative Impact on Survival Independent of Decreased Myelopoiesis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4653-4653 ◽  
Author(s):  
Heather A. Leitch ◽  
Hatoon Ezzat ◽  
Meaghan D. Rollins ◽  
Dominic H.C. Wong ◽  
Chantal S. Leger ◽  
...  
Keyword(s):  
Negative Impact ◽  
Bone Marrow Failure ◽  
Prognostic Score ◽  
Performance Status ◽  
Iron Chelation ◽  
Primary Myelofibrosis ◽  
Ecog Performance Status ◽  
Platelet Counts ◽  
Transfusion Requirements ◽  
Rbc Transfusion

Abstract Primary myelofibrosis (PMF) is a myeloproliferative disorder characterized by progressive bone marrow failure, extramedullary hematopoiesis and risk of progression to blast phase (BP). Many PMF patients (pts) require red blood cell (RBC) transfusions, risking iron overload (IOL)-related organ dysfunction. Pts with myelodysplastic syndrome and RBC transfusion dependence (TD) have worse overall survival (OS), which may be improved by iron chelation therapy (ICT). To assess the effect of TD and ICT on survival in PMF, we reviewed 30 pts seen from 1985 to 2007 with a marrow biopsy confirmed diagnosis. 21 pts were male and 9 female and median age at Dx was 66.5 (range 43–84) years (y). ECOG Performance Status; 0, n=13; 1, n=9; 2, n=7; 3, n=1. WBC count was <4.0 or >30x109/L at diagnosis in 5 pts, and hemoglobin (Hb) <100G/L in 14. Karyotype in 13 pts: normal, n=11; del (6)(q25), n=1; complex, n=1. Lille Prognostic Score was: 0, n=10; 1, n=11; 2, n=4. 20 pts were RBC-TD with total units (U) transfused: 1–20, n=6; 21–50, n=3; >50, n=11. Initial PMF treatment was: supportive care, n=21; low-dose chemotherapy, n=4; immunomodulatory, n=3; splenectomy, n=2. Clinical evidence of IOL, n=14 total: CHF, n=4; liver disease, n=3; endocrine, n=3; ferritin ≥1000 ug/L at Dx, n=6. Baseline features that differed between transfusion-independent (TI) and TD and between non-ICT-TD and ICT pts: total RBCU transfused (p=0.0001 and p=0.03) and evidence of IOL (p=0.003 and p=0.06), respectively. 5 pts received ICT for a median of 75.7 (range 2.9–117) months (mo); 4 received desferrioxamine (DFO) 0.5–3g by subcutaneous infusion 12 h/d, 5 d/wk and 2 received deferasirox (1 switched from DFO). At a median follow-up (FU) of 58.8 (0.1–243.7) mo, 2 non-ICT pts and 1 ICT pt progressed to PMF-BP; 2 received chemotherapy and all 3 died of progressive BP within weeks. Median OS for all pts, TI, TD and ICT pts was: 102.1 (14.4–243.7) mo; not reached at 204.9 mo; 60.8 (14.4–243.7) mo and 83.6 (60.8–202.9) mo and 5y OS was 67%; 100%; 55% and 66% respectively (p=0.014 for TD vs. TI). Factors significant for OS were: RBC-TD (p=0.014, hazard ratio [HR] 43.6, confidence intervals [CI] 41–46.2); increasing RBC transfusion requirement (TR; 2 fold change in RBCU/4wk; p=0.018, HR 5.0 [4.3–5.7]); Hb<100G/L (p=0.03, HR 3.8, [3.2–4.4]); total RBCU transfused (p=0.0001, HR 1.3 [1.0–1.6]). 12 TD pts (60%) died: cardiac, n=3; infection, n=3; bleeding, n=2 (1 ICT pt); PMF-BP, n=3; unknown, n=1. Initial/pre-ICT mean ± standard error (se) ferritin was 2337±1038ug/L in ICT pts and 506±466ug/L in non-ICT pts, and FU ferritin decreased in ICT pts to 1902±428ug/L (p=0.03) and was 824±445ug/L in non-ICT pts (p=NS). Initial and FU neutrophil counts (NC) in ICT pts were a mean ±se of 4.7±1.6 and 5.0±1.7 vs. 7.2±1.5 and 20.6±7.7 x109/L in non-ICT pts; platelet counts (PLTC) were 432±89; 527±208; 293±50; and 203±36 x109/L respectively and RBCU transfused/4 wk were 2.3±0.6; 3.3±0.8; 1.3±0.3; 1.8±0.4 (p=NS for all and for TI vs. TD NC and PLTC). In conclusion, 67% of pts with PMF developed RBC-transfusion dependence, which portended worse OS. However, there was no significant decrease in neutrophil or platelet counts or increase in RBC transfusion requirements. This suggests the effect of TD on OS was not from impaired myelopoiesis alone, and that there may be an impact of IOL secondary to TD on outcome. Prospective studies of ICT in PMF pts are warranted.

Lenalidomide-Induced Cytopenias: Relationship to Hematologic Improvement in Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 821-821 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Jaroslaw P. Maciejewski ◽  
Aristoteles Giagounidis ◽  
Kenton Wride ◽  
Robert D. Knight ◽  
...  
Keyword(s):  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Myelodysplastic Syndromes ◽  
Odds Ratio ◽  
Lower Risk ◽  
Multivariate Analyses ◽  
Mechanisms Of Action ◽  
Erythroid Response ◽  
Transfusion Independence ◽  
Rbc Transfusion

Abstract Background: Lenalidomide (LEN) is effective in MDS patients (pts) with or without deletion (del) 5q cytogenetic abnormalities. Common toxicities include neutropenia and thrombocytopenia. Both occurrence of cytopenias and response to LEN is more common in pts with the del 5q abnormality. This study analyzes whether development of treatment-related cytopenias is associated with response to LEN in lower-risk MDS pts. Methods: Transfusion-dependent, low/int-1-risk MDS pts were enrolled in the MDS-003 (del 5q pts) and MDS-002 (non-del 5q pts) studies. Pts were treated with 10 mg LEN (daily or 21/28 days). Baseline thrombocytopenia was defined as a platelet (plt) count <150,000/mm3; neutropenia as an absolute neutrophil count (ANC) <2000/mm3 (grade 1–4 using the CTC v2.0). Cytopenias were assessed within the first 8 weeks of LEN therapy, and given functional definitions based on frequency tables. Response was assessed using International Working Group criteria. Results: Of 147 evaluable pts in MDS-003, 59 (40%) had thrombocytopenia, 59 (40%) neutropenia, and 84 (57%) neutropenia and/or thrombocytopenia according to baseline labs. Of 210 evaluable pts in MDS-002, 69 (33%) had thrombocytopenia and 81 (39%) neutropenia at baseline. For both studies, median age was 71 and 72 years and MDS duration was 2.5 and 2.2 years, respectively. RBC transfusion independence (TI) was achieved by 99 pts (67%) in MDS-003 (List et al. NEJM 2006) and 56 pts (26%) in MDS-002. For pts with del 5q, development of thrombocytopenia correlated with TI, regardless of baseline plt count (p=0.005). Comparing pts who had a ≥50% drop vs those who did not, TI was achieved in 76% vs 47% of pts without baseline thrombocytopenia and in 67% vs 38% of pts with thrombocytopenia, respectively. Similar results held for pts without baseline neutropenia: 82% whose ANC fell ≥75% achieved TI, compared to 56% whose ANC fell <75% (p=0.018). In pts with baseline neutropenia, ANC drop did not correlate with TI (p=0.75). In pts with any baseline cytopenia, those whose ANCs fell by ≥75% and/or plt by ≥50% were more likely to achieve TI than those whose counts did not drop substantially, controlling for baseline cytopenias (71% vs. 60%, p=0.024). In multivariate analyses, both a treatment-related ANC drop ≥75% (odds ratio [OR]=2.68, p=0.04) and a plt drop ≥50% (OR=2.79, p=0.05) remained associated with TI in MDS-003. Neither was associated with duration of TI response, though there was a trend with drop in ANC (hazard ratio=2.04, p=0.06). In contrast, for pts without del 5q (MDS-002), no correlation exists between TI and drop in plt count (p=0.36 for patients without and p=0.16 for those with baseline thrombocytopenia), drop in ANC (p=0.43 for those without and p=0.44 for those with baseline neutropenia), or development of either cytopenia. No correlation with TI could be established in MDS-002 for drops of 25%, 50%, or 75% within 4, 8, or 16 weeks of therapy, in both univariate and multivariate analyses. Conclusions: In MDS pts with del 5q, treatment-related thrombocytopenia, and neutropenia in those with normal baseline ANCs, correlate with response to LEN, supporting the link between suppression of the del 5q clone and erythroid response. This correlation was not observed in non-del 5q MDS pts, indicating alternate mechanisms of action of LEN.

Iron Chelation in Regularly Transfused Patients with Aplastic Anemia: Efficacy and Safety Results from the Large Deferasirox EPIC Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 439-439 ◽  
Author(s):  
Jong Wook Lee ◽  
Sung-Soo Yoon ◽  
Zhi Xiang Shen ◽  
Hui-Chi Hsu ◽  
Arnold Ganser ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Aplastic Anemia ◽  
Iron Reduction ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Efficacy And Safety ◽  
Iron Intake ◽  
Liver Iron ◽  
Transfusion Requirements

Abstract Background: Patients with aplastic anemia (AA) can be effectively treated with bone marrow transplantation or immunosuppressive/immunomodulatory therapy, but many will require repeated blood transfusions to manage symptoms of severe anemia and are subsequently at risk of accumulating excessive body iron. Reduction in iron burden across a range of transfusion-dependent anemias, including AA, has been previously demonstrated with deferasirox (Exjade®). More recently, the EPIC trial enrolled the largest cohort of patients with AA undergoing iron chelation to date. The efficacy and safety of deferasirox in these patients are presented. Methods: Enrolled patients had transfusion-dependent AA and serum ferritin (SF) levels of □1000 ng/mL, or &lt;1000 ng/mL with a history of multiple transfusions (&gt;20 transfusions or 100 mL/kg of red blood cells) and an R2 MRI-confirmed liver iron concentration (LIC) &gt;2 mg Fe/g dry weight. Deferasirox was administered at an initial dose of 10–30 mg/kg/day depending on transfusion requirements, with dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) based on assessment of SF trends and safety markers indicative of iron toxicity. SF was assessed every 4 weeks and the primary efficacy endpoint was the change at week 52 from baseline. Safety assessments included adverse event (AE) monitoring and assessment of laboratory parameters. Results: In total, 116 AA patients (67 males, 49 females; mean age 33.3 years) were enrolled. Median baseline SF was 3254.0 ng/mL; patients received a mean of 115.8 mL/kg of blood in the year prior to enrollment. Approximately two-thirds of patients (68.1%) had received no prior chelation therapy. Of those who had, patients received deferoxamine (DFO; n=31, 26.7%) or combination DFO/deferiprone (n=6, 5.2%). After 12 months, median SF decreased significantly by 964.0 ng/mL from baseline median of 3254.0 ng/mL (P=0.0003). This occurred at an average actual deferasirox dose of 17.6±4.8 mg/kg/day. The median change in SF from baseline was –970.0 ng/mL (P&lt;0.0001; 3263.0 ng/mL [baseline]; 0.20 mg/kg/day [mean iron intake]) in patients receiving a mean actual deferasirox dose &lt;20 mg/kg/day (n=75) and −883.8 ng/mL (P=0.27; 3238.0 ng/mL [baseline]; 0.29 mg/kg/day [mean iron intake]) in those receiving 20–&lt;30 mg/kg/day (n=40). Overall, 88 patients (76%) completed the study; reasons for discontinuation included AEs (n=13, 11%), consent withdrawal (n=6, 5%), lost to follow-up (n=1, 1%) and various other reasons (n=3, 3%). In addition, five patients (4%) died during the study (one death related to pneumonia, three due to sepsis and one as a result of hepatic adenoma rupture). No death was suspected by investigators to be treatment related. The most common drug-related AEs (investigator-assessed) were: nausea (n=26, 22%), diarrhea (n=18, 16%), rash (n=13, 11%), vomiting (n=10, 9%), dyspepsia (n=9, 8%), abdominal pain (n=7, 6%), upper abdominal pain (n=7, 6%), and anorexia (n=7, 6%). Most AEs were mild or moderate in severity (&gt;95%). 29 patients (25.0%) had an increase in serum creatinine &gt;33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. One patient (0.9%) had an increase in alanine aminotransferase (ALT) that exceeded &gt;10xULN on two consecutive visits; ALT levels were elevated in this patient at baseline. Conclusions: Over a 1-year treatment period, deferasirox significantly reduced iron burden in transfusion-dependent, iron overloaded patients with AA. Despite the high iron burden, most patients had received no prior chelation therapy, indicating a clear need for iron chelation in this patient population. Overall, deferasirox was generally well tolerated in these AA patients with the majority of AEs being mild to moderate.

Lenalidomide in Myelodysplastic Syndromes with 5q Deletion. Results From the Italian National Cancer Registry

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3850-3850
Author(s):  
Cristina Mecucci ◽  
Andrea Roncadori ◽  
Roberta La Starza ◽  
Francesco Arcioni ◽  
Alessandro Levis ◽  
...  
Keyword(s):  
Median Time ◽  
Myelodysplastic Syndromes ◽  
Normal Karyotype ◽  
Hematological Toxicity ◽  
Laboratory Findings ◽  
Transfusion Independence ◽  
Drug Agency ◽  
Conventional Cytogenetics ◽  
Grade 3 ◽  
5Q Deletion

Abstract Abstract 3850 Background: Lenalidomide (LEN) is available in Italy for patients with intermediate-1- and low-risk myelodysplastic syndromes (MDS) associated with 5q deletion (5q-) since October 2008, based on a local disposition of the Italian Drug Agency (AIFA) issued according to a national law (Law 648/96). LEN is an oncological drug subject to intensive monitoring and, when it is prescribed in MDS, physicians are requested to enter the patient into a registry, which is entirely web-based. Methods: This observational, retrospective, multicenter study (registered at www.clinicaltrials.govasNCT01347944) has enrolled patients at 40 centres of 43 authorized in Italy. The study was approved by the ethic committee of each participating institution. The purpose was to analyse data available in the Registry and to integrate them with additional clinical and laboratory findings by filling up new e-forms in all cases with MDS and 5q- receiving LEN from October 31st, 2008 until the present. Diagnosis, treatment, follow-up and re-evaluation of patients were considered. Results: Study population included patients pre-treated and not pre-treated, with or without the integration form at the end of treatment. Pre-treated were defined as patients who were given LEN (from 1 to 12 cycles, median 3) before entering the AIFA registry. 158 patients (42 pre-treated and 116 not pre-treated) were eligible for this preliminary analysis. Median age was 75 (range, 38–89 years); 6 patients were younger than 50. There were 108 females (68.35%) and 50 males (31.6%) (table). Hematological findings evaluated at diagnosis were: hemoglobin (<8.5g/dL, 43% and >8.5g/dL, 57%), macrocytosis (MCV >98 fL, 54.4%), platelet count (<140×109/L, 24.7%; between 140 and 400×109/L, 56.3%; >400×109/L, 19%). Median white blood cell count was 4× 103/L with 54% neutrophils. Bone marrow blasts ≤5% were found in 75.9% of cases. The 5q- was detected by conventional cytogenetics in 131/158 cases (82.9%): it was isolated in 110 cases, associated with one additional in 15, and in complex karyotypes in 6. In 2 cases with normal karyotype and in 25 cases with failed cytogenetics the 5q- was demonstrated by fluorescence in situ hybridization (FISH). These cases could not be grouped as isolated or non-isolated. Patients received LEN at a daily dose of 10mg or 5 mg for 21 of 28 days as the starting dose. The dose and schedule was adjusted mainly based on blood count and hematological toxicity. Median time on treatment was 15.5 months (range, 1–45). Major and minor criteria for hematological and cytogenetic response are under evaluation. Transfusion independence at 6 months was reached in 77/103 cases (74.75%). Hematological toxicity could be evaluated in 148 cases. A total of 555 neutropenia events (36% grade 3 and 12.9% grade 4) and 422 thrombocytopenia events (10.9% grade 3 and 6.16% grade 4) were seen. Among 69 evaluable cases, 11 (15.9%) developed acute myeloid leukemia. In this group the median age was 72 (range, 62–85) and there were 4 males and 7 females. The median number of LEN cycles was 6 (range, 2–31). The median time from diagnosis of MDS was 34 months (range, 4–68). Chromosome 5q- at diagnosis was demonstrated by conventional cytogenetics in 8 cases (6 isolated and 2 with one additional change) and by FISH in 3. Comments: The Italian Drug Agency (AIFA) Registry provided us with a large series of MDS cases with 5q- to investigate appropriatness of LEN prescription and management. As expected LEN was successful to obtain transfusion independence in this patient population. Hematological toxicity was manageable. The number of cases with leukemic evolution is in line with data reported in the literature. These cases will be further investigated. Disclosures: Mecucci: CELGENE: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document