Elderly Myelodysplastic Syndromes Research Articles

New data shed light on Y-loss-related pathogenesis in myelodysplastic syndromes.

Loss of the Y-chromosome (LOY) is described as both a normal age-related event and a marker of a neoplastic clone in hematologic diseases. To assess the significance of LOY in myelodysplastic syndromes (MDS), we determined the percentage of LOY in clonal CD34+ peripheral blood cells in comparison to normal CD3+ T-cells of 27 MDS patients using fluorescence in situ hybridization (FISH) analysis. Results were compared with the percentage of LOY in CD34+ and CD3+ cells of 32 elderly men without hematologic diseases and in 25 young blood donors. While LOY could not be detected in CD3+ cells of young men, it was observed in CD3+ cells of elderly men without hematologic diseases (2.5% LOY) as well as in CD3+ cells of elderly MDS patients (5.8% LOY). The percentage of CD34+ cells affected by LOY was significantly higher in MDS patients compared to elderly men without hematologic diseases (43.3% vs. 13.2%, P = 0.005), indicating that LOY has an age-related basis but is also associated with MDS. Furthermore, we aimed to define a threshold between age- and disease-associated LOY in MDS. Statistical analysis revealed that a value of 21.5% LOY in CD34+ peripheral blood cells provided the best threshold to discriminate between these two conditions in MDS. We conclude that LOY is clonal in a substantial number of MDS based on an age-related predisposition.

The Impact of Different TP53 Mutations on Outcome in Patients with Myelodysplastic Syndromes (MDS)

outcomes among elderly Medicare-enrolled MDS patients in the USA. Methods: Patients were identified from the SEER-Medicare database using these criteria: 1) ICD-O-3 codes for MDS, 2) diagnosed between 1/1/2005 and 12/31/2011, 3) aged 66 years at diagnosis, and 4) enrolled in Medicare Parts A and B continuously through death or end of study (12/31/2012). Medicare payments were used to estimate costs and adjusted to 2012 US dollars. Cumulative costs were calculated as per Zhao et al (Stat Med 2007). To estimate MDS-specific costs, costs in a matched group of cancerfree Medicare beneficiaries were subtracted from costs in MDS cohort. Comorbidities were used to calculate a modified Elixhauser comorbidity and the disability status scores. KaplaneMeier estimates described overall survival (OS) probabilities from date of diagnosis. Hazard ratios (HR) were estimated using multivariate Cox proportional hazard models. Tests were two-sided with an alpha of 0.05. Results: Out of 8,564 eligible patients, 86.7% were white, 53.0% males, 52.5% 80 years at diagnosis, and 15.7% received hypomethylating agents ([HMA]. Twoand 3-year observed OS rates were 48.7% and 40.6%, respectively. The 2-year MDS-specific cost per patient ranged between $43,950 and $83,961 across 12 states. Factors associated with improved 2-year survival included female gender, non-white ethnicity, younger age at diagnosis, refractory anemia (RA) and RA with ring sideroblasts subtypes, pre-diagnosis health costs, lower Elixhauser comorbidity and lower disability status scores. In contrast, zip code-median household income level, HMA use, and the two-year state-level MDS-specific costs [Reference: low costs, HR for medium costs 1.02, 95%CI, 0.93-1.12, P-value1⁄40.74, and for high costs HR was 0.99, 95%CI, 0.92-1.06, P-value1⁄40.73] were not associated with the 2-year OS probabilities. Additionally, the 2-year MDS-specific costs were also not associated with the 3-year OS probabilities. Conclusions:Medicare expenditure on elderly MDS patients varied significantly across different states in the USA during the two years post-diagnosis, but was not related to the 2-year or 3-year survival. The disconnection between cost and outcome warrants additional research.

Accuracy of physician assessment of treatment preferences and health status in elderly patients with higher-risk myelodysplastic syndromes

Higher-risk myelodysplastic syndromes (MDS) are rarely curable and have a poor prognosis. We investigated the accuracy of physicians’ perception of patients’ health status and the patients’ preferences for involvement in treatment decisions.We examined 280 newly diagnosed higher-risk elderly MDS patients paired with their physicians. Survey tools included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Control Preference Scale.Overall concordance was 49% for physician perception of patient preferences for involvement in treatment decisions. In 36.4% of comparisons there were minor differences and in 14.6% there were major differences. In 44.7% of the patients preferring a passive role, physicians perceived them as preferring an active or collaborative role. Absence of the patient's request for prognostic information (P=0.001) and judging the patient as having a poor health status (P=0.036) were factors independently associated with the physicians’ attitude toward a lower degree of patient involvement in clinical decisions. Agreement on health status was found in 27.5% of cases. Physicians most frequently tended to overestimate health status of patients who reported low-level health status.The value of decision aid-tools in the challenging setting of higher-risk MDS should be investigated to further promote patient-centered care.

Hospitalization rates in elderly, newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) patients treated with azacitidine.

e18040 Background: Azacitidine is a common treatment for elderly AML and MDS patients. We describe rates of hospitalization in an older cohort of AML or high-risk MDS patients initially treated wit...

Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome: Impact of Age and Conditioning

Introduction: Myelodysplastic syndromes (MDS) are one of the main indications for allogeneic hematopoetic cell transplantation (HCT). With the introduction of reduced intensity conditioning regimens (RIC) this curative therapy is increasingly used in elderly (≥60 years) or comorbid patients (pts).Methods: Here we retrospectively analyzed data obtained in 81 consecutive adult MDS patients (f=32, m=49) that underwent allogeneic HCT using either myeloablative (MAC) regimens (Busulfan (Bu)/Cyclophosphamid (Cy) (n=13), Cy (n=1); Cy/Total Body Irradiation (TBI) 12Gray (n=6)) or RIC (FLAMSA/Fludarabin (Flu)/Bu (n=3); Flu/Bu (n=28); Flu/TBI (n=5); Flu/Thiotepa/Melphalan (Mel) (n=2); Flu/Treosulfan (n=12), FLAMSA/Bu/Cy (n=1), Flu/Cy/TBI (n=2), Flu/Mel (n=2)). For graft versus host disease (GVHD) prophylaxis, calcineurin inhibitor combined with mycophenolate mofetil (n=24) or methotrexate (n=41) and anti-thymocyte globulin (n=60) were used.Results: Median age at first diagnosis of patients was 53 years (range 21-72). Pts were grouped in 2 age categories: pts <60 years (group A, n=57) and >60 years (group B, n=24). Pts suffered from MDS/CMML 5q, n=2; CMML I, n=3; CMML II, n=2; RAEB I, n=21; RAEB II, n=21; RCMD, n=27; RCUD, n=2. Median IPSS score in group A and B was 1.4. 32% of group A and 35% of group B had an IPSS Score below 2. Mean HTC-CI in group A was 1.4, in group B 1.7. Grafts either from matched related (A, n=18, B, n=2), matched unrelated (MUD; A, n=25, B, n=13) or mismatched unrelated (MMUD; A, n=7, B, n=9) donors were used. Conditioning in group A was MAC (n=20) or RIC (n=31) whereas all patients in B received RIC. No significant age-associated influence was observed with regard to median survival (A, 44 months; B, 26 months; p=0.7) or estimated 3 year overall survival (OS) (A, 33%; B, 19%; p=0.3). Median observation time of patient alive was 40 months (range 3-168 month). Cumulative incidences of non-relapse mortality adjusted for relapse as competing risk showed no significant difference for group A and B. Progression free survival was not significantly different between the groups (A, 20 months; B 12 months; p=0.25). Kaplan-Mayer Analysis showed no difference in OS between risk groups; however, progression free survival was significantly lower in the group with IPSS >2 (7 vs 22 months, p=0.02). Within 100 days, neither in A nor B non-relapse mortality (NRM) was documented. The use of a MMUD appeared to have a negative but not significant influence in older pts on OS (3-year OS in A: MUD 75% vs. MMUD 25%, p=1.00; B: MUD 100% vs MMUD 0%, p=0.2). Incidence of GvHD ≥II was in 14% vs. 6% in A and B. Incidence of chronic GVHD was 42% in A (limited=12, extensive=12) and 37% in B (limited=4, extensive=5).Conclusion: RIC represents a promising treatment option in elderly MDS pts and allows for allogeneic HCT even in comorbid pts. Age had no negative impact on survival. Interestingly, IPSS score has an influence on progression free survival in patients. DisclosuresNo relevant conflicts of interest to declare.

Recombinant human erythropoietin in very elderly patients with myelodysplastic syndromes: results from a retrospective study

Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80-99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6-10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) patients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p = 0.004), ferritin <200 ng/ml (p = 0.017), Hb >8 g/dl (p = 0.034), and a high-dose rHuEPO treatment (p = 0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5-68.4) in responders versus 30.6 months (95 % CI 7.3-53.8) in resistant patients (p = 0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.

Incidence of Myelodysplastic Syndrome in Japan

BackgroundMyelodysplastic syndromes (MDS) are a diverse group of clonal hematopoietic stem cell malignancies that primarily affect the elderly. Although the incidence of MDS in western countries has been well investigated, little is known about the incidence in Asian populations.MethodsTo identify the incidence of MDS in Japan, we used population-based registry data from 1993 to 2008. The data represented 33.1% of the Japanese population. A total of 7995 patients were reported to the registry with newly diagnosed MDS during the study period.ResultsMedian age at diagnosis was 76 years. Incidence sharply increased with age, particularly in those aged over 70 years. The most recent crude incidence rate of MDS was 3.8 (95% CI 3.6–4.1) cases per 100 000 for men and 2.4 (95% CI 2.2–2.6) cases per 100 000 for women in 2008. Age-adjusted incidences of MDS in 2008, standardized by the world standard population, were 1.6 and 0.8 cases per 100 000 for men and women, respectively, while incidences standardized by the 1985 Japanese population were 2.5 and 1.2 cases per 100 000 for men and women, respectively.ConclusionsOur study reveals that some elderly patients suffer from MDS in Japan, but the incidence is lower than in Western countries. In current clinical practice, many elderly MDS patients are treated with supportive therapy based on an incomplete diagnosis, suggesting that the incidence estimated in this study might still be substantially underestimated. Accurate evaluation of the health impact of MDS requires evaluation of the mortality of the disease, continued surveillance, and improvement in the quality of cancer registry data.

A case of secondary leukemia subsequent to myelodysplastic syndromes successfully treated with azacitidine.

Elderly patients with secondary acute myeloid leukemia (AML) following myelodysplastic syndrome (MDS) are often medically unfit for or resistant to chemotherapy, and their prognosis is dismal. In the present paper, we reported a case of secondary leukemia following MDS in an 80-year-old male patient who was deemed unfit for chemotherapy owing to his old age and poor physical condition. Despite a high tumor burden, treatment with AZA exerted a remarkable response, leading to an immediate cytoreduction in our case. Our results suggest that AZA can be an attractive therapeutic option for elderly MDS or AML patients, offering adequate efficacy and high tolerability.

Age Does Not Predict Outcomes For Elderly Patients With Myelodysplastic Syndromes Undergoing Hematopoietic Stem Cell Transplantation With Reduced-Intensity Conditioning

Background The National Care Determination for allogeneic hematopoietic stem cell transplantation (allo HSCT) for the treatment of myelodysplastic syndromes (MDS) stated that there is an absence of convincing evidence that allo HSCT improves health outcomes. A prospective data-gathering trial sponsored by the CIBMTR is ongoing; however, until such results are available, retrospective methods specifically comparing older populations are illustrative. Methods We analyzed outcomes for older patients with MDS undergoing HSCT with reduced intensity conditioning (RIC) at the Dana-Farber/BWH with uniform conditioning and graft versus host disease (GVHD) prophylaxis regimens from 2001 to 2011. Patients with CMML were excluded. Those aged 60-65, and those ≥ 66 were compared to assess overall survival (OS), progression free survival (PFS), and other HSCT-related outcomes. Aiming to build a better prognostic score using its significant components, we also assessed the association of the IPSS-R at transplantation as well as each of its components with OS, and fit multivariable Cox regression models with the new prognostic score as well as age. Results We identified 67 patients aged 60 or older who underwent RIC HSCT for MDS. All patients received fludarabine and intravenous busulfan as conditioning, and peripheral blood stem cells. GVHD prophylaxis included tacrolimus/rapamycin +/- MTX. The median age was 64 (60-74) years, and the majority (64%) had unrelated donors. 60% had advanced MDS (IPSS-R high risk or very high risk), 46% had poor risk cytogenetics, and 67% had high or very high disease risk index (DRI). The median age for the 60-65 group was 63; the median age for the ≥ 66 group was 69. We found no significant differences in PFS or OS by age category, as shown below (also see figure): In addition, rates of 6-month grade III-IV GVHD (p=.45) and 2-year incidence of cGVHD (p=0.78) did not significantly differ. The IPSS-R performed only modestly in predicting 4-year OS for this older cohort (p=.20); however, a new 3-level score (including collapsed cytogenetic categories, dichotomous platelet count [ ≥ 50 or &lt; 50], percent blasts in marrow and dichotomous ANC) performed better (p=.008; see figure). In two multivariable models, one that included the IPSS-R and another that included the new score, age was not a significant predictor of OS (p=.78 and .77 respectively). Conclusions Our data suggest that age alone should not limit availability of RIC HSCT for patients with MDS, as older patients in our elderly cohort faired similarly to younger ones with respect to important HSCT-related outcomes. Our new prognostic score, if validated, may be able to help risk-stratify patients. Finally, continued efforts are needed to reduce relapse in high-risk elderly MDS patients. Disclosures: No relevant conflicts of interest to declare.

Should elderly patients with higher-risk myelodysplastic syndromes undergo allogeneic hematopoietic stem cell transplantation?

Evaluation of: Koreth J, Pidala J, Perez WS et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J. Clin. Oncol. 31(21), 2662–2670 (2013).Myelodysplastic syndromes (MDS) include a group of hematopoietic malignancies characterized by dysplastic changes, ineffective hematopoiesis and variable risk of leukemic progression. At diagnosis, 86% of MDS patients are ≥60 years. Azacitidine, the only drug that prolongs life in high-risk (HR)-MDS patients, adds a median of only 9.5 months to life. Allogeneic stem cell transplantation (alloSCT) remains the only potentially curative approach. Despite recent improvements including use of reduced intensity conditioning (RIC) that decrease transplant-related mortality, alloSCT continues to be used rarely in elderly MDS. There is paucity of data regarding outcomes of RIC alloSCT in elderly MDS patients, especially in direct comparison with azanucleosides. In this paper, the authors discuss the recent Markov decision analysis by Koreth et al. in which investigators demonstrated superior survival of patients with HR-MDS aged 60–70 years who underwent RIC alloSCT in comparison with those who were treated with azanucleosides.

Efficacy of Oral Cytarabine Ocfosfate and Etoposide in the Treatment of Elderly Patients with Higher-Risk Myelodysplastic Syndromes Compared to That in Elderly Acute Myeloid Leukemia Patients

Background: Elderly acute myeloid leukemia (AML) patients and patients with higher-risk myelodysplastic syndromes (MDS) have a much poorer prognosis than younger patients despite intensive chemotherapy. Methods: Ten patients with higher-risk MDS and 12 patients with AML over 65 years of age were enrolled into this study and received oral induction therapy with cytarabine ocfosfate and etoposide. Results: The therapy response rates were 60% in the MDS group and 41.7% in the AML group. The difference in overall survival among MDS and AML patients was not statistically significant. The difference in the median survival times of the responsive and nonresponsive groups, which included MDS and AML patients, was statistically significant (790 and 174 days, respectively). Conclusions: Based on a comparison of the data of this therapy in elderly higher-risk MDS patients versus elderly AML patients, we conclude that this therapy is well tolerated and can be cost-effective and useful for higher-risk MDS in elderly patients.

Utilization Patterns of Iron Chelation Therapy in Transfusion-Dependent Myelodysplastic Syndrome Patients Enrolled in Medicare Part D.

AbstractAbstract 3178 Background:Anemia is present in up to 90% of patients (pts) with myelodysplastic syndromes (MDS), with as many as 40% developing red blood cell (RBC) transfusion-dependency. Though studies have reported clinical utility of iron chelation therapy (ICT) in MDS pts, its impact on overall survival from prospective studies is yet to be demonstrated. Reflective of this therapeutic equipoise and lack of uniform recommendations in the published guidelines, clinical utilization practices vary significantly. To better understand the utilization patterns of ICT, we conducted a retrospective analysis of a large transfusion-dependent MDS cohort enrolled in Medicare Part D from 2005 to 2008. Methods:MDS pts were identified using ICD-9 CM codes (1 inpatient or 2 outpatient) from a 100% Medicare sample. Pts meeting a minimum transfusion threshold of cumulative 20 packed RBC were considered “ICT eligible”. The study cohort consisted of ICT-eligible pts enrolled in Medicare Part D, allowing characterization of oral drug use. The observation period began the week (wk) after pts met the transfusion threshold and lasted until death or end of study. Transfusion use was captured based on specific Health Care Common Procedure Coding System (HCPCS) or revenue codes. Use of drugs, including ICT, was captured using specific HCPCS and National Drug Code (NDC) codes in Medicare Part B and D claims. Age at MDS diagnosis, race, and sex were determined from Medicare enrollment files. Logistic regression models were used to identify correlates of ICT use. Results:Among 125,290 MDS pts, 12,691 met the minimum transfusion threshold and were considered ICT eligible. Of those, 5,079 (40%) were enrolled in Medicare Part D and constituted the study cohort. In the study cohort, 65.6% of pts were ≥75 years old, 90% white, 47.8% males, and 13.9% had a poor predicted performance status (PS). MDS was classified as low-risk in 13.1%, 5q deletion-associated in 2.1%, high-risk in 6.9%, and not otherwise specified (NOS) in 77.9%. Common comorbidities included coronary artery disease (47.9%), congestive heart failure [CHF] (43.6%), cardiac conduction disorders or arrhythmias (44%), and renal disease (35.5%). The median follow-up was 95 wks (range 2–208). Pts were transfused a median of 13 (range 0–369) additional RBC units during the observation period. Among the entire study cohort, 793 patients (15.6%) received ICT; 513 (10.3%) received only deferasirox (DFX), 187 (3.8%) received only deferoxamine (DFO), and 93 (1.9%) received both. Median time from cohort entry to ICT initiation was 18 wks. The average dose for DFO was 2,932 mg/wk and for DFX, 1300 mg daily, relative to recommended levels of 10,000–14,000 mg/wk for DFO and 1,000–2,000 mg/daily for DFX. Median ICT therapy duration was 11 wks (1–168) for DFO, and 19 wks (1–139) for DFX. ICT was received for <26 wks in 60% of DFO and 57% of DFX users. Among ICT users, 71%, 37%, and 21%, received erythropoiesis-stimulating agents, hypomethylating agents (HMAs) and lenalidomide, respectively, during the observation period. No significant differences in ICT use were seen between low-risk, 5q deletion, and high-risk MDS pts (13.9% vs. 11.5% vs. 15.8%, P=0.52). In multivariate analysis using Cox proportional hazard models, the following were negatively associated with probability of receiving of ICT: age ≥ 90 years (Hazard ratio [HR] 0.557, 95%CI 0.347–0.894), female gender (HR 0.781, 95%CI 0.672–0.906), poor predicted PS (HR 0.725, 95%CI 0.541–0.972), history of CHF (HR 0.817, 95%CI 0.679–0.982), cardiac conduction disorders and arrhythmias (HR 0.824, 95%CI 0.694–0.979), and renal disease (HR 0.758, 95%CI 0.632–0.910). The likelihood of receiving ICT was higher among African American pts relative to whites (HR 1.579, 95%CI 1.157–2.156), residents of the South 2000 Census region (HR 1.27, 95%CI 1.005–1.604), and those pts receiving HMAs (HR 1.026, 95%CI 1.018–1.033) or lenalidomide (HR 1.007, 95%CI 1.003–1.012). Conclusions:Overall, ICT utilization rates among elderly transfusion-dependent MDS pts and among those with significant comorbidities were low. Also, ICT therapy was more likely to be of short duration among the elderly. Utilization rates were higher for DFX than DFO, and doses closer to recommended levels for DFX than DFO, likely reflecting greater ease of administration. Disclosures:Baer:Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Sasane:Novartis Pharmaceuticals: Employment. Paley:Novartis: Employment. Davidoff:Celgene: Equity Ownership, Research Funding; National Institutes of Health: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding.

Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome

AbstractAllogeneic hematopoietic stem cell transplantation (SCT) is well accepted as a curative treatment approach for younger patients with myelodysplastic syndrome (MDS) and has become one of the most frequent indications for allogeneic SCT as reported to the Center for International Blood and Marrow Transplant Research. However, MDS patients are usually elderly with a median age of approximately 75 years at diagnosis. Large register studies have confirmed the feasibility of the procedure in elderly MDS patients; and in the register of the European Group for Blood and Marrow Transplantation, one-third of the allogeneic transplant procedures for MDS were performed in 2010 in patients older than 60 years. Despite its curative potential, its role in the treatment of elderly MDS patients is less defined. Because of the inherent complications of the transplantation leading to treatment-related mortality and the risk of relapse, a careful calculation of the benefit for each patient is mandatory, taking into account comorbidities, disease status, donor selection, and effective nontransplant therapies. Prospective multicenter studies are needed to define optimal intensity of the conditioning regimen, timing of transplantation within a treatment algorithm, including drug-based therapies, and posttransplant strategies to reduce the risk of relapse.

Regional variation in treatment costs and survival for elderly patients with myelodysplastic syndromes.

6628 Background: Myelodysplastic syndromes (MDS) occur primarily in the elderly (≥65 years). The expected 5-year cost for an elderly MDS patient tops $63,200 in 2009 US$. This study assessed regional variation in the cost of care and survival for elderly MDS patients. Methods: Using the Surveillance Epidemiology and End Results–Medicare data, we identified primary MDS patients aged 66-99 years diagnosed from 2001-2007, had continuous fee-for-service coverage for Parts A and B, and had no history of other cancer. We assigned patients to Dartmouth Atlas of Health Care Hospital Referral Regions (HRRs) based on their residence at time of diagnosis. We also selected controls from a 5% sample of Medicare beneficiaries without cancer and matched controls 1:1 to patients by HRR, age, sex, pre-diagnosis cost and comorbidity. All Medicare claims through 2009 were tallied, and MDS-related costs were defined as the difference between the payments for a patient and a matched control. Results: With 6244 patients in 73 HRRs, the average 3-year MDS-related cost varied across HRRs, ranging from $12,900 to $83,600 (2009 US$). Patients in high-spending regions had more comorbidities and higher Medicare costs before diagnosis and were more likely to be racial minorities and live in lower-income areas. Three-year survival ranged from 13.0% to 62.1%. However, there was no significant correlation between 3-year costs and 3-year survival (ρ=-0.06, p=0.61). The hazard ratios (HR) for higher spending regions compared to the lowest-expenditure region were near 1, after controlling for covariates including MDS subtype (2nd quartile: HR=1.03, 95% CI: 0.94-1.12; 2nd quartile: HR=1.04, 95% CI: 0.95-1.14; 4th quartile: HR=0.98, 95% CI: 0.90-1.08). Conclusions: We observed considerable regional variation in Medicare expenditure on elderly MDS patients during the first 3 years post-diagnosis. However, patients in higher cost regions had similar 3-year survival to patients in lower cost regions. Given the substantial economic burden of MDS and Medicare’s current fiscal challenges, it is important to further assess the factors associated with higher regional costs and to improve the care of MDS patients in a cost-efficient way.

The challenge of individualised risk assessment and therapy planning in elderly high-risk myelodysplastic syndromes (MDS) patients

Myelodysplastic syndromes (MDS) represent one of the most frequent and serious haematologic diseases of the elderly. Effective therapies exist ranging from best supportive care to haematologic stem cell transplantation (HSCT). Decision making, however, is rather complex in this group of patients because ageing is a multidimensional process involving not only physiological changes but also changes in functional, social, emotional and cognitive capacities. All these factors can have a significant impact on the efficacy and tolerability of a potential therapy and therefore have to be thoroughly assessed before deciding on individual treatment regimens. Risk assessment tools are available both to classify the stage and prognosis of MDS and to meet the needs of elderly patients. A tool explicitly focussing on elderly MDS patients, however, is still missing. The current report approached this issue by combining the well established MDS-risk score ‘International Prognostic Scoring System’ (IPSS) with the ‘Multidimensional Geriatric Assessment’ (MGA). As decision making is most complex in high-risk MDS patients, the new algorithm is presented exemplarily for this group of patients. In a first step, MDS-related risk is identified using IPSS, in a second step, patients are assigned to one of three risk categories of the MGA (go-go/fit, slow-go/vulnerable, no-go/frail). While go-go patients might be subjected to therapies comparable to those given to younger patients, in no-go patients, a palliative therapy combined with best supportive care will probably be most appropriate. In slow-go patients, age-related life expectancy taken from public age statistics should be compared to the MDS-related life expectancy. Based on this combined assessment procedure and also on treatment tolerance in terms of the expectations/wishes of the patient and his/her family, an individualised therapeutic approach should be developed. Specific treatment recommendations for these three groups of patients are given, including HSCT, azanucleosides and best supportive care. To illustrate its practicability, i.e. the implementation of the novel algorithm in clinical practice, the case of an elderly high-risk MDS patient is presented and discussed in detail. This new algorithm will facilitate the identification of the very particular needs and conditions of elderly MDS patients in clinical practice. Based on this, individually tailored therapeutic approaches can be developed—the prerequisite for the best possible clinical outcome.

Iron chelation therapy in myelodysplastic syndromes: we need more evidence, not more guidelines

Iron chelation therapy in myelodysplastic syndromes: we need more evidence, not more guidelines

Phase II Trial of Sorafenib in Myelodysplastic Syndrome: A Single Institution Experience

Abstract 5021 Background:Myelodysplastic Syndrome (MDS) represents a heterogeneous group of stem cell abnormalities characterized by cytopenias and dysplastic cells in both the bone marrow (BM) and peripheral blood. The goals of treatment in MDS are symptom control, to improve the quality of life along with survival and to decrease the risk of progression to Acute Myeloid Leukemia (AML). One of the many biologic hallmarks of MDS is increased angiogenesis in the BM. Sorafenib is a dual kinase inhibitor of both RAF and vascular endothelial growth factor (VEGF). This study proposed using Sorafenib as an anti-VEGF molecule in patients with MDS. The primary endpoint was efficacy of Sorafenib in MDS with secondary endpoints of safety, progression-free survival, and relapse rate. Methods:Patients 18 years or older with a diagnosis of primary or therapy-related myelodysplastic syndrome or myelodysplastic/ myeloproliferative disorders as defined by the WHO, with adequate renal and hepatic function, and ECOG 0–2 were eligible irrespective of prior number of therapies. After informed consent, Sorafenib was prescribed at a dose of 400 mg orally twice a day and was administered on days 1–28 of a 28-day cycle. Patients were evaluated for hematological response using IWSG criteria after 2 cycles and then every 3 cycles thereafter. Toxicity was assessed using the NCI CTCAE V3.0 criteria. Results:N=19 patients were screened from March 2006 to present date. Three patients were ineligible due to the presence of AML in the BM done at the time of screening. In the 16 evaluable patients, median age was 71 years, with 10 males and 6 females. When classified by IPSS, four patients had low-risk, five had intermediate 1, six patients had Intermediate 2, and one patient had high risk MDS. Eight patients had normal karyotype, two had a trisomy 8 and six patients had poor-risk, complex cytogenetics. The median number of prior therapies was two, with 10 patients having received prior hypomethylating agent (azacitidine, decitabine, or both), eight patients having received an ESA (darbepoeitin or erythropoietin), and six patients having received an immunomodulatory agent (thalidomide, lenalidomide). Of note, three patients had secondary MDS i.e. previous exposure to chemotherapy and radiation.Of the 16 patients, one patient is currently on therapy. Seven patients were on the study drug for < 1 month and either stopped the drug on their own or requested to be taken off the trial secondary to toxicity. The mean duration of treatment was 3.6 months and all patients developed some grade 2 or grade 3–4 toxicity, mainly non-hematologic. The most common toxicities that led to discontinuation of the drug included: fatigue, constipation, and neuropathy. One patient developed pancreatitis, and another developed myositis requiring inpatient admission. Four patients on trial had progressive disease i.e. transformed to AML within a mean of 4 months of therapy. Two patients had stable disease, and nine patients refused further BM biopsy to assess response to therapy. Conclusion:While, small numbers limits the study, it provides us with valuable information that Sorafenib 400mg orally BID in elderly MDS patients is fairly toxic. Almost 50% of study patients were on Sorafenib for <1 month and withdrew from the trial due to side effects of fatigue, constipation and diarrhea. Sorafenib may benefit a selective group of patients with myeloid disorders and FLT3-ITD mutations. Disclosures:No relevant conflicts of interest to declare.

Quality of life, physical function and MRI T2* in elderly low-risk MDS patients treated to a haemoglobin level of ≥120 g/L with darbepoetin alfa ± filgrastim or erythrocyte transfusions

Anaemia in low-risk myelodysplastic syndromes (MDS) is associated with reduced quality of life (QoL). Response to treatment with erythropoietin ± granulocyte colony-stimulating factor (G-CSF) is associated with improved QoL, but whether transfusion therapy with higher haemoglobin (Hb) target levels has similar effects is unknown. The objective for this prospective phase II Nordic multicentre trial was to assess QoL, response rate and physical function in elderly anaemic MDS patients treated to a target Hb level of >120 g/L. Thirty-six elderly patients with low- and intermediate-1 risk MDS received darbepoetin (DA) 300 μg/wk, with the addition of G-CSF if no response. If the Hb target was reached at 16 wk, treatment was maintained until week 26. Remaining patients were transfused to reach the target level for at least 8 wk. Twenty-seven patients completed the study. Response rate to DA ± G-CSF was 67% in evaluable patients and 56% according to intention to treat. Eighteen patients reached the target Hb level according to protocol. QoL scores for fatigue, dyspnoea, constipation, and physical, role and social functioning improved significantly during study, with similar results for transfused and untransfused patients. Maintaining Hb >120 g/L did not confer a higher transfusion rate, once the target was reached. In two of fourteen patients, magnetic resonance imaging T2* indicated cardiac iron overload, however, without association with ferritin levels. In elderly anaemic MDS patients, an increment in haemoglobin is associated with improved QoL, whether induced by growth factor treatment or transfusion therapy.

Myelodysplastic Syndrome Patients Younger Than 50 Years: Epidemiological Data and Clinical Features

AbstractAbstract 4976Less than 10% of patients with myelodysplastic syndromes (MDS) are younger than 50 years. It is yet unknown the exact role of prognostic scoring systems in this subset, because clinical relevant data were derived from large series of elderly patients. Undefined are also the clinical features of younger patients exposed to potential mutagens due to occupational reasons. Aim of our study was to report and analyze one of the largest series of young MDS, in terms of prognosis and overall survival. Ninety-one patients with MDS aged less than 50 years consecutively diagnosed and conservatively treated form July 1983 and December 2009 are reported and compared with the whole population of elderly MDS patients. Median age at diagnosis was 44 years (range 21–50). Sex M/F ratio was 0.68. According to FAB criteria there were 56 patients with refractory anemia (RA), 3 with refractory anemia with ringed sideroblasts (RARS), 22 with refractory anemia with excess of blasts (RAEB), 5 with refractory anemia with excess of blasts in transformation (RAEB-t) and 5 with chronic myelomonocytic leukemia (CMML). Revised 2008 WHO classification reclassified low risk patients as pure RA (only 8 patients), refractory unilineage cytopenia (RCUD, refractory thrombocytopenia, 2 patients) and refractory cytopenia with multilineage dysplasia (RCMD, 45 patients). RAEB patients were classified as RAEB-1 (11 patients) and RAEB-2 (11 patients). Eighty-five patients had evaluable cytogenetic analysis: the most frequent karyotypic change was trisomy 8 (10.5%), followed by monosomy 7 (5%). Among this cohort, 23 patients had occupational exposure to potential mutagens (more frequently benzene and its derivates and solvents): in the exposed group there was a male predominance (16/7), a higher frequency of RCMD (52%) and a higher frequency of monosomy 7 (13%). At a median follow-up of 72 months, 22 patients (24 %) evolved to acute leukemia: among the exposed cohort, a higher frequency of AML evolution was observed (39% vs 19% of non-exposed). IPSS categorization showed 30 patients as low risk, 35 patients as intermediate-1, 14 patients as intermediate-2 and 4 patients as high risk, with intermediate-1 risk being the more commonly detected. Both the intermediate-2 and high risk according to IPSS, together with age cut-off above 40 years, male sex, FAB and WHO high-risk definition and exposure to carcinogens during lifetime, were found to be predictive of a shorter overall survival. Comparison of younger patients with elderly MDS population followed in the same Institute over the same period of time, showed statistical differences in survival (88 months for younger vs 24 months for elderly MDS, p<0.0001), sex ratio (p=0.002), FAB and WHO classification (both p=0.03). These results suggest that MDS in patients aged less than 50 years could be identified as a distinct category and that aggressive approaches should rarely be recommended for younger patients belonging to the low and intermediate-I risk groups. Disclosures:No relevant conflicts of interest to declare.

A Phase II Study of Low Dose Intravenous Clofarabine for Elderly Myelodysplastic Syndrome Patients Who Have Failed 5-Azacytidine

AbstractAbstract 4955Based on the observations of changes in DNA methylation status of various tumor suppressor genes, epigenetic targeting of myelodysplastic syndrome (MDS) with DNA hypomethylating agents are currently used for these patients. However, only up to 40% of the patients respond to these treatments. Therapeutic options for non-responders or responders whose disease progresses while on therapy are very limited. Based on our recent findings that low concentration clofarabine induced DNA hypomethylation, we carried out a Phase II study of elderly MDS patients who had failed 5-azacytidine (5-aza) therapy to determine the efficacy and toxicities of low dose intravenous clofarabine (ClinicalTrials.gov Identifier NCT00700011). Patients in Cohort 1 received intravenous clofarabine at 10 mg/m2/day and patients in Cohort 2 5 mg/m2/day for 5 days, each infusion given over 2 hours and each cycle repeated every 4 to 8 weeks, depending on the rate of bone marrow recovery. Eight patients were planned for each of the treatment dose. The patients were treated until disease progression or intolerable toxicities. The International Working Group response criteria were used.The study was closed after 10 patients were treated. Of the 10 patients (6 males and 4 females) treated, ei8 received 10 mg/m2/day (Cohort 1) of clofarabine and 2 patients 5 mg/m2/day (Cohort 2). The median age was 73 years (range 65–78). Five patients had only received 5-aza prior to being treated with clofarabine while the other 5 patients had also received other therapy (lenolidomide and decitabine).Three patients received 1 cycle, 4 patients received 2 cycles, 1 patient received 3 cycles and 2 patients received 4 cycles of clofarabine. The following responses were observed in the 9 evaluable patients: 1 CR (11%), 1 PR (11%), 2 HI (22%), 3 SD and 2 PD. The overall response rate was 44% in this group of elderly patients. All responses were observed in patients who received clofarabine 10 mg/m2/day. Response rate of 67% (4/6) was observed in patients with low risk MDS (IPSS < 1). In contrast, all 3 evaluable patients with high risk/Int.-2 MDS showed disease progression. The median time to response was 6 weeks (range 4–6 weeks) and 1 cycle of clofarabine. The patient who achieved a CR remained in CR for 14 months. The 2 patients who achieved HI both restored the erythroid-responsiveness to recombinant erythropoietin and became transfusion-independent, both for 10 months (1 patient received only 1 cycle and the other patient 2 cycles of clofarabine). As of July 31, 2010, diseases in all four responders have relapsed/progressed. The median duration of response was 10 months (range 5–14).Despite using low doses of clofarabine, severe and prolonged pancytopenia was observed in all 10 patients. All 10 patients needed considerable blood and platelet transfusions. Eight of these ten patients also needed hospitalization for neutropenic fever. Of the 22 cycles of clofarabine administered, there were a total of 13 hospital admissions with 100 hospital days. A total of 169 units of irradiated packed red blood cells (median 10 units/cycle; range 1.5–14 units/cycle) and 211 units of irradiated single donor platelets (median 10 units/cycle; range 2–30.5 units/cycle) were used. One patient died, within 2 weeks of completing cycle 1 of clofarabine, from intracranial bleed despite intensive support of severe thrombocytopenia with aggressive platelet transfusion. This patient was already thrombocytopenic prior to starting clofarabine and had a history of severe thrombocytopenic gastrointestinal bleed prior to starting on clofarabine. Nonhematologic toxicities occurred very infrequently and were mainly Grade 2 or lower. In all cases, clofarabine was discontinued due to either disease progression (2 patients) or toxicities (8 patients). With a median follow-up of 7.5 months (range 0.5–22), the overall survival for the whole group was 50%.In conclusion, elderly MDS patients, especially those with low risk disease, who have failed 5-aza may respond to low dose clofarabine. However, even at the low doses used in this study, bone marrow toxicity was significant. It remains to be determined whether the dose of clofarabine can be reduced further to minimize toxicities without compromising efficacy in this group of patients. Future studies should investigate the role of low dose clofarabine in low risk MDS patients.Study supported by Genzyme Corporation, Cambridge, MA, USA Disclosures:No relevant conflicts of interest to declare.