NCCN: Continuing Education
Accreditation Statement
This activity is designated to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.
NCCN designates this educational activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.
National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-15-005-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/62682; and 4) view/print certificate.
Release date: March 6, 2015; Expiration date: March 6, 2016
Learning Objectives
Upon completion of this activity, participants will be able to:
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Integrate into professional practice the updates to the NCCN Guidelines for Myelodysplastic Syndromes
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Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Myelodysplastic Syndromes
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Refinements to the method of prognosis and stratification of patients with myelodysplastic syndromes (MDS) and to the treatment regimens are indicated by the revisions to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myelodysplastic Syndromes.1 Previously, the International Prognostic Scoring System (IPSS) and WHO Prognostic Scoring System (WPSS), which are based on morphology, cytogenetics, and the presence of cytopenias in patients with MDS, were the most frequently used.2,3 Recently, in a joint multinational study, termed the IWG-PM project, the IPSS was revised (IPSS-R)4 and has shown improved prognostic capability. This has initiated a transition from earlier scoring systems to the IPSS-R.
Conventional karyotyping remains the keystone for diagnosis of MDS5,6; however, refined cytogenetic categories have been given greater weight in the IPSS-R,7 adding credence to the importance of
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
The NCCN Guidelines are updated at least once per year, which is necessary to provide the most up-to-date treatments for clinical practice. One recent discussion regarding cancer treatment as a whole is the incorporation of risk/benefit and financial cost strategies. Although evaluation of the risks and benefits of individual treatments has always factored into patient care, a greater number of treatment protocols are now available across which clinicians must evaluate the advantage to patient outcome, possibility of adverse events, effect on quality of life, and degree of patient financial burden before determining the appropriate treatment. The financial impact of treating patients with MDS according to the NCCN Guidelines has been reported.8 The latest full version of these guidelines is available on the NCCN Web site (NCCN.org).
Universal Implementation of the IPSS-R
The IPSS-R was derived from analysis of a large dataset including 7012 patients from multiple international institutions. The IPSS-R defines 5 risk groups (very low, low, intermediate, high, and very high), versus the 4 groups in the IPSS, and provides more detailed cytogenetic abnormalities and subgroups (see MDS-5, page 263). Specifically, 16 cytogenetic abnormalities versus the previous 6 are identified, and the cytogenetic subgroups are refined to comprise 5 versus 3 risk groups.4,7 The newer classification separates the original designation of “marrow blasts <5%” into 2 subgroups, defined as “marrow blasts ≤2%” and “marrow blasts >2% to <5%.” Furthermore, the IPSS-R includes a depth of cytopenias measurement, defined with cutoffs for hemoglobin levels, platelet counts, and neutrophil counts. Age, performance status, serum ferritin, lactate dehydrogenase, and β2-microglobulin provide additional differentiating features related to survival but not for acute myeloid leukemia (AML) evolution. It should
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
Several retrospective studies have demonstrated the validity of the IPSS-R. In a database analysis of patients with MDS from a single institution (N=1088), median overall survival (OS) according to IPSS-R risk categories was 90 months for very low, 54 months for low, 34 months for intermediate, 21 months for high, and 13 months for very high (P<.005).9 The median follow-up in this study was 70 months. The IPSS-R was also predictive of survival outcomes among patients who received therapy with hypomethylating agents (n=618). A significant survival benefit with azacitidine was shown only for the high and very high IPSS-R risk groups compared with patients not receiving azacitidine (median survival, 25 vs 18 months; P<.028; median survival, 15 vs 9 months; P=.005, respectively). Significantly longer OS with allogeneic hematopoietic stem cell transplantation (HSCT) was only observed for patients at high risk (median survival, 40 vs 19 months without HSCT; P<.005) and very-high risk (median survival, 31 vs 12 months without HSCT; P<.005).9
Another multicenter study reviewed patients with MDS who received either best supportive care only (n=1314), induction chemotherapy (n=214), or allogeneic transplant (n=167) to compare the prognostic value of the IPSS-R with the IPSS, WPSS, and Duesseldorf score.10 The IPSS-R could clearly distinguish risk categories and was better than the 3 other scoring systems for identifying patient survival and risk of AML evolution. The distribution of patients among the IPSS-R groups was similar to that of the cohort in the original design of the IPSS-R. Overall, patients who had worse prognosis and were formerly categorized as lower risk by the IPSS could be identified as higher risk by the IPSS-R. Similarly, the IPSS-R ascribed to lower-risk category patients who had a more favorable prognosis than was predicted by the IPSS.10
As part of a larger study to identify predictive factors for patients receiving allogeneic HSCT, Della
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
Additional studies have confirmed the value of the IPSS-R in treated and untreated patients.9–11,13–18 Because more accurate risk stratification by the IPSS-R compared with the IPSS and WPSS has been demonstrated,16 the IPSS-R categorization is preferred. Although implementation of the IPSS-R has already occurred in many institutions, it has not fully transitioned into community practice, the drug approval process, or transplant decision applications. Community hospitals may find calculating the IPSS-R to be complex, particularly the inclusion of cytogenetic abnormalities; however, online calculators (http://advanced.ipss-r.com) and SmartPhone apps are available for the IPSS-R to facilitate its use. A difficulty in universally adopting the IPSS-R to the drug approval process is that it could influence how drugs are used if they were originally approved under the IPSS. Lastly, the complication with applying the IPSS-R to the decision algorithms in terms of when to recommend transplant was discussed. These algorithms are currently based on the IPSS or WPSS.19,20 Although institutions are predicted to switch over to the IPSS-R as more data become available, a paucity of data remains regarding transplant. Recently, data were presented on the potential utility of using the
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
NCCN Guidelines Insights: Myelodysplastic Syndromes, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 3; 10.6004/jnccn.2015.0038
During this transition period, before more uniform prognostic risk stratification is accepted by the field, keeping multiple prognostic scoring systems in the algorithms seems prudent. Therefore, each algorithm page that refers to treatment pathways based on prognostic category indicates category designations for IPSS, IPSS-R, and WPSS (see MDS-10 and MDS-11, pages 265 and 266, respectively). The algorithms address certain recommendations in the footnotes. For cases in which a patient is managed as lower risk but fails to experience response, the recommendation is to then move to a higher-risk management strategy.
Appropriate Incorporation of Frequent Mutations in Patient Evaluation
In recent years, several gene mutations have been identified among patients with MDS that may, partly, contribute to the clinical heterogeneity of the disease course, and thereby influence prognosis. A large variety of gene mutations will be present in most patients with newly diagnosed MDS, including most patients with normal cytogenetics. The NCCN Panel does not recommend molecular testing to establish a diagnosis of MDS. Comparable abnormalities have been described in apparently normal individuals. Also, in patients with a confirmed diagnosis of MDS using standard diagnostic criteria only, a limited number of the abnormalities have established prognostic significance. Several studies examining large numbers of MDS marrow or peripheral blood samples have identified more than 40 recurrently mutated genes, with more than 80% of patients harboring at least 1 mutation.23–26 Frequent mutations in MDS-associated genes that are likely to be indicative of clonal hematopoiesis are listed in the NCCN Guidelines (see MDS-7, page 264). These genes can be categorized into several groups: (1) transcription factors (TP53, RUNX1, ETV6); (2) epigenetic regulators and chromatin-remodeling factors (TET2, DNMT3A, ASXL1, EZH2, IDH1/2); (3) pre-mRNA splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2); and (4) signaling molecules (NRAS, CBL, JAK2, SETBP1).
The most frequently mutated genes were TET2, SF3B1, ASXL1, DNMT3A, SRSF2, RUNX1, TP53, U2AF1, EZH2, ZRSR2, STAG2, CBL, and NRAS, although no single mutated gene was found in more than a third of patients. Several of these gene mutations are associated with adverse clinical features, such as complex karyotypes (TP53), excess bone marrow blast proportion (RUNX1, NRAS, and TP53), and severe thrombocytopenia (RUNX1, NRAS, and TP53). Despite associations with clinical features considered by prognostic scoring systems, mutations in several genes hold independent prognostic value. Mutations of TP53, EZH2, ETV6, RUNX1, and ASXL1 have been shown to predict decreased OS in multivariable models adjusted for IPSS or IPSS-R risk groups in several studies of distinct cohorts.23,26 Within IPSS risk groups, a mutation in 1 or more of these genes identifies patients whose survival risk resembles that of patients in the next highest IPSS risk group (eg, the survival curve for INT-1–risk patients with an adverse gene mutation was similar to that of patients assigned to the INT-2–risk group by the IPSS).23 When applied to patients stratified by the IPSS-R, the presence of a mutation in 1 or more of these 5 genes was associated with shorter OS for patients in the low- and intermediate-risk groups.26 Thus, the combined analysis of these gene mutations and the IPSS or IPSS-R may improve on the risk stratification provided by these prognostic models alone. Mutations of ASXL1 have also been shown to carry independent adverse prognostic significance in chronic myelomonocytic leukemia.27,28 Other mutated genes have been associated with decreased OS, including DNMT3A, U2AF1, SRSF2, CBL, PRPF8, SETBP1, and KRAS.23,26,29–32 Mutations of SF3B1 have been associated with a more favorable prognosis, but this may not be an independent risk factor.26,33
Mutations of TP53 are strongly associated with complex and monosomal karyotypes. However, approximately 50% of patients with a complex karyotype have no detectable TP53 abnormality and have an OS comparable to that of patients with noncomplex karyotypes. Therefore, TP53 mutation status may be useful for refining the prognosis of these patients typically considered to have higher-risk disease.23,34 Patients with del(5q), either as an isolated abnormality or often as part of a complex karyotype, have a higher rate of concomitant TP53 mutations.35,36 These mutations are associated with diminished response or relapse after treatment with lenalidomide.37,38 In these cases, TP53 mutations may be secondary events and are often present in small subclones that can expand during treatment. More sensitive techniques may be required to identify the presence of subclonal, low-abundance TP53 mutations before treatment.
Although several recurring genetic mutations have been identified in studies of patients with MDS and may be useful for assessing prognosis, their possible utility in diagnosing MDS has not been established. Some mutations may prove useful after further analysis, but many of the same mutations have been identified in elderly patients who do not have MDS,39 and thus their use for diagnosis is not currently recommended.
As noted in the algorithms, for patients categorized as intermediate risk by the IPSS-R, prognostic factors may affect treatment. This may be seen in patients who are initially treated on a lower-risk scale but do not experience a response to treatment. The presence of these mutations may direct the clinician to a higher-risk treatment strategy (see MDS-10, page 265). Other patients who may benefit from mutational analysis are those who experience no response to hypomethylating agents and move to a clinical trial. These tests may be useful in determining an appropriate clinical trial that targets the specific lesion.
Significant discussion occurred regarding how to appropriately include mutations into the NCCN Guidelines. Although mutational analysis is not recommended for use in routine clinical circumstances, additional testing could be useful in some clinical situations, as described earlier. For these circumstances in which the identification of mutations would be clinically beneficial, the panel recommends the use of sites established for molecular analysis.
Cost-Effective Care
Patients with MDS require evaluation for short-term and long-term disease-related and treatment-related side effects, with continuous monitoring for disease progression or the development of complications, such as infections. Several therapeutic options are available for patients with MDS, depending on their specific clinical features as outlined in the NCCN Guidelines. The NCCN Guidelines for MDS should be consulted regarding criteria for treatment selection. However, occasionally clinicians must choose among these options based on individual patient factors. In these situations, it may also be appropriate to be aware of and consider cost-effective care. Optimization of treatment may often result in a concurrent reduction in cost.
One treatment that has received more recent analysis is the evaluation of red blood cell (RBC) transfusion practices in patients who develop symptomatic anemia. The recommendation to keep transfusions to the minimal amount of units necessary to relieve symptoms or restore normal hemoglobin levels was highlighted in an article from the ASH Choosing Wisely Campaign.40 Similar verbiage has been added to the 2015 NCCN Guidelines for MDS (see MDS-B, page 267).41–43 Furthermore, there are inherent risks associated with transfusions, including transfusion-related reactions, transfusion-associated circulatory overload, bacterial contamination and viral infections, and iron overload. Iron overload is a particular concern for patients with MDS who receive frequent transfusions over several years. In these patients, iron overload may occur, causing an excess of iron deposition in the liver, heart, skin, and endocrine organs, resulting in potential complications and the need to consider iron chelation medications to prevent or stabilize such adverse events (see MDS-B, page 267).
The standard method to attempt to decrease RBC transfusions in symptomatic anemic patients with MDS without del(5q) is the use of recombinant erythropoietin.1 Dosing and response prediction (ie, relatively low serum recombinant erythropoietin, clinical risk status) are important considerations for use of this drug. The cost-effectiveness can also be evaluated among hematopoietic cytokines, specifically epoetin alpha (EPO) and darbepoetin for the treatment of symptomatic anemia. Based on the 2009 NCCN Guidelines for MDS, the annual cost of EPO ranged from $26,076 to $52,176 compared with the cost of darbepoetin, which ranged from $41,904 to $87,300.8 The variability in cost reflects the spectrum of acceptable dosages. However, further studies have compared lower doses of darbepoetin with EPO and have shown that 200 mcg of darbepoetin every 2 weeks has equivalent effectiveness as 40,000 U of EPO.44,45 Using these values instead of a range, the cost of EPO would be approximately $18,824 compared with the cost of darbepoetin, which is estimated to be $15,132. Therefore, dosage is a significant consideration when comparing the cost. Furthermore, darbepoetin can be administered less frequently than EPO, providing a significant value in terms of quality of life. Because both of these drugs may be coadministered with a granulocyte colony-stimulating factor, the cost of the additional cytokine does not ultimately affect the comparison of these hematopoietic cytokines.
Another option for reducing RBC transfusions in patients with MDS is the use of lenalidomide. The FDA has approved lenalidomide for the treatment of transfusion-dependent anemia in patients with del(5q) classified as having low- or INT-1-risk MDS (see MDS-10, page 265). Clinical trial data have shown that lenalidomide treatment can result in transfusion independence in a substantial proportion of these patients (≈60%–70%).46,47 Studies have shown the relative safety of lenalidomide in these patients and improved quality of life outcomes in randomized clinical trials.48,49 Thus, lower-risk patients with del(5q) chromosomal abnormalities and symptomatic anemia should receive lenalidomide. However, lenalidomide should be avoided in those with a clinically significant decrease in neutrophil or platelet counts.50
Although the cost of lenalidomide is higher than other treatment regimens, the expense is partially offset by the reduction in the number of transfusions and the duration of transfusion independence. The estimated annual cost for lenalidomide when given 21 days per month is $66,204, based on the 2009 NCCN Guidelines.8 A publication evaluating the cost-effectiveness of lenalidomide versus best supportive care from Goss et al51 also showed a similar cost for lenalidomide of $63,385. In this study, the cost of best supportive care was approximately $54,940 annually. Factors that were included in the overall cost were the annual primary cost of the intervention, annual cost of transfusions when on the intervention, and annual cost of drug-related complications. Additionally, comparison for health outcomes showed that 67.0% of patients given lenalidomide were transfusion-free versus only 8.9% of patients receiving best supportive care. Although not quantifiable from a financial benefit, quality of life is generally greater with lenalidomide treatment because of a fewer number of treatments and the oral bioavailability of lenalidomide.
Another treatment cost associated with RBC transfusion includes the use of iron chelation drugs. The NCCN MDS Panel recommends consideration of deferoxamine subcutaneously for 5 to 7 days per week or daily deferasirox orally to decrease iron overload (aiming for a target ferritin level <1000 ng/mL) in the following IPSS low- or INT-1–risk patients: (1) those who have received or are anticipated to receive more than 20 RBC transfusions, particularly for lower-risk patients; (2) those for whom ongoing RBC transfusions are anticipated; and (3) those with serum ferritin levels greater than 2500 ng/mL (see MDS-B, page 267). Although both iron chelators are a category 2A recommendation, choosing between the 2 options may involve several factors. The prescribing information for deferasirox contains a black box warning pertaining to the increased risks for renal or hepatic impairment/failure and gastrointestinal bleeding in certain patients.52 It is recommended that patients on deferasirox therapy be closely monitored via measurement of serum creatinine and/or creatinine clearance and liver function tests before initiation of therapy, and regularly thereafter. The oral availability of this formulation makes it easier to administer than deferoxamine for most patients in terms of patient compliance. The subcutaneous administration of deferoxamine is more time-intensive and entails indirect costs associated with administration of the drug. The direct cost of deferasirox annually was estimated to be $46,008 per year compared with deferoxamine, which was estimated at $21,048 per year.8 However, although deferasirox has a higher direct cost, the associated indirect costs must be evaluated to determine overall financial burden. In a study from the United Kingdom, deferasirox was evaluated to be more cost-effective than deferoxamine in patients with lower-risk, transfusion-dependent MDS based on the cost of the drug, cost of administration and monitoring, and quality-of-life outcomes, with the last serving as the key driver for improved quality-adjusted life-years.53 Taken together, both iron chelators have advantages and disadvantages that must be considered for each patient before a treatment is determined.
Another treatment option that has been evaluated for cost-effectiveness involves the use of hypomethylating agents. Currently, azacitidine and decitabine are considered to be therapeutically similar, although the improved survival of higher-risk patients treated with azacitidine compared with control patients in a phase III trial supports the preferred use of azacitidine in this setting (see MDS-10 and MDS-11, pages 265 and 266, respectively).54–57 Azacitidine can be administered subcutaneously or intravenously compared with decitabine, which requires an intravenous infusion with clinic or hospital admission. Studies have shown that indirect costs for decitabine are higher (if the azacitidine is given subcutaneously), further adding to the expense.58 Indirect costs were calculated to include hospitalization, management of side effects, physician visits, and use of erythropoiesis-stimulating agents.58 Selection of the hypomethylating agent azacitidine may result in a lower expense but equivalent benefit if azacitidine is given subcutaneously.8,58
Comparison between cancer treatments must evaluate whether any one treatment confers a benefit in survival or quality of life compared with another. If a benefit is observed, it should be weighed against the treatment cost. As discussed earlier, this does not necessarily mean a patient will be accepting a poorer prognosis or less valuable treatment. Historically, the NCCN Guidelines have excluded cost of a treatment from their deliberations on recommendations in order to provide an unbiased set of treatment options. However, this means that options in the current guidelines that are considered equivalent based on patient outcomes may not be equivalent when cost is a factor. Future iterations of the guidelines may involve cost evaluation, but until then, clinicians should be advised to consider cost, not in exchange for reduced care, but rather to prevent any undue financial burden to the patient.
Conclusions
The yearly revision of the NCCN Guidelines is a reflection of the rate at which cancer research advances treatment. However, the advances must be conveyed to clinicians and patients to allow integration into practice, and to enable patients to advocate regarding their own care. The most recent update has highlighted advances in the prognostic and diagnostic aspects of MDS. Treatment options have also been updated and modified to provide improved patient care. Future directions must endeavor to address the increasing cost of care. With the current state of health care, strategies to improve clinical treatment should also incorporate economic strategies.
References
- 2.↑
Greenberg P, Cox C, LeBeau MM et al.. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079–2088. Erratum in Blood 1998;2091:1100.
- 3.↑
Malcovati L, Germing U, Kuendgen A et al.. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007;25:3503–3510.
- 4.↑
Greenberg PL, Tuechler H, Schanz J et al.. Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes. Blood 2012;120:2454–2465.
- 5.↑
Wang H, Wang XQ, Xu XP, Lin GW. Cytogenetic evolution correlates with poor prognosis in myelodysplastic syndrome. Cancer Genet Cytogenet 2010;196:159–166.
- 6.↑
de Souza Fernandez T, Ornellas MH, Otero de Carvalho L et al.. Chromosomal alterations associated with evolution from myelodysplastic syndrome to acute myeloid leukemia. Leuk Res 2000;24:839–848.
- 7.↑
Schanz J, Tuchler H, Sole F et al.. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol 2012;30:820–829.
- 8.↑
Greenberg PL, Cosler LE, Ferro SA, Lyman GH. The costs of drugs used to treat myelodysplastic syndromes following National Comprehensive Cancer Network Guidelines. J Natl Compr Canc Netw 2008;6:942–953.
- 9.↑
Mishra A, Corrales-Yepez M, Ali NA et al.. Validation of the revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes. Am J Hematol 2013;88:566–570.
- 10.↑
Neukirchen J, Lauseker M, Blum S et al.. Validation of the revised international prognostic scoring system (IPSS-R) in patients with myelodysplastic syndrome: a multicenter study. Leuk Res 2014;38:57–64.
- 11.↑
Della Porta MG, Alessandrino EP, Bacigalupo A et al.. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R. Blood 2014;123:2333–2342.
- 12.↑
Alessandrino EP, Della Porta MG, Bacigalupo A et al.. WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood 2008;112:895–902.
- 13.↑
Ades L, Lamarque M, Raynaud S et al.. Revised-IPSS (IPSS-R) is a powerful tool to evaluate the outcome of mds patient treated with azacitidine (AZA): the Groupe Francophone Des Myelodysplasies (GFM) experience [abstract]. Blood 2012;120:Abstract 422.
- 14.
Cermak J, Mikulenkova D, Brezinova J, Michalova K. A reclassification of myelodysplastic syndrome (MDS) patients of RAEB-1 subgroup according to IPSS-R improves discrimination of high risk patients and better predicts overall survival. A retrospective analysis of 49 patients [abstract]. Blood 2012;120:Abstract 4957.
- 15.
Messa E, Gioia D, Evangelista A et al.. High predictive value of the revised International Prognostic Scoring System (IPSS-R): an external analysis of 646 patients from a multiregional Italian MDS registry [abstract]. Blood 2012;120:Abstract 1702.
- 16.↑
Voso MT, Fenu S, Latagliata R et al.. Revised International Prognostic Scoring System (IPSS) predicts survival and leukemic evolution of myelodysplastic syndromes significantly better than IPSS and WHO Prognostic Scoring System: validation by the Gruppo Romano Mielodisplasie Italian Regional Database. J Clin Oncol 2013;31:2671–2677.
- 17.
Valcarcel D, Sanz G, Ortega M et al.. Identification of poor risk patients in low and intermediate-1 (Int-1) IPSS MDS with the new IPSS-R index and comparison with other prognostic indexes. A study by the Spanish Group of MDS (GESMD) [abstract]. Blood 2012;120:Abstract 702.
- 18.↑
Warlick ED, Hirsch BA, Nguyen PL et al.. Comparison of IPSS and IPSS-R scoring in a population based myelodysplastic syndromes (MDS) study [abstract]. Blood 2012;120:Abstract 3841.
- 19.↑
Malcovati L, Hellstrom-Lindberg E, Bowen D et al.. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 2013;122:2943–2964.
- 20.↑
Kroger N. Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome. Blood 2012;119:5632–5639.
- 21.↑
della Porta MG, Alessandrino EP, Jackson CH et al.. Decision analysis of allogeneic stem cell transplantation in patients with myelodysplastic syndrome stratified according to the revised International Prognostic Scoring System (IPSS-R) [abstract]. Blood 2014;124:Abstract 531.
- 22.↑
Ok CY, Hasserjian RP, Fox PS et al.. Application of the international prognostic scoring system-revised in therapy-related myelodysplastic syndromes and oligoblastic acute myeloid leukemia. Leukemia 2014;28:185–189.
- 23.↑
Bejar R, Stevenson K, Abdel-Wahab O et al.. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011;364:2496–2506.
- 24.
Bejar R, Stevenson KE, Caughey BA et al.. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 2012;30:3376–3382.
- 25.
Papaemmanuil E, Gerstung M, Malcovati L et al.. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013;122:3616–3627.
- 26.↑
Haferlach T, Nagata Y, Grossmann V et al.. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014;28:241–247.
- 27.↑
Itzykson R, Kosmider O, Renneville A et al.. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013;31:2428–2436.
- 28.↑
Patnaik MM, Itzykson R, Lasho TL et al.. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia 2014;28:2206–2212.
- 29.↑
Walter MJ, Ding L, Shen D et al.. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 2011;25:1153–1158.
- 30.
Graubert TA, Shen D, Ding L et al.. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet 2012;44:53–57.
- 31.
Thol F, Kade S, Schlarmann C et al.. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 2012;119:3578–3584.
- 32.↑
Makishima H, Yoshida K, Nguyen N et al.. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet 2013;45:942–946.
- 33.↑
Patnaik MM, Lasho TL, Hodnefield JM et al.. SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value. Blood 2012;119:569–572.
- 34.↑
Bejar R, Papaemmanuil E, Haferlach T et al.. TP53 mutation status divides MDS patients with complex karyotypes into distinct prognostic risk groups: analysis of combined datasets from the International Working Group for MDS-Molecular Prognosis Committee [abstract]. Blood 2014;124:Abstract 532.
- 35.↑
Sebaa A, Ades L, Baran-Marzack F et al.. Incidence of 17p deletions and TP53 mutation in myelodysplastic syndrome and acute myeloid leukemia with 5q deletion. Genes Chromosomes Cancer 2012;51:1086–1092.
- 36.↑
Jadersten M, Saft L, Smith A et al.. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 2011;29:1971–1979.
- 37.↑
Mallo M, Del Rey M, Ibanez M et al.. Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and mutations. Br J Haematol 2013;162:74–86.
- 38.↑
Jadersten M, Saft L, Pellagatti A et al.. Clonal heterogeneity in the 5q-syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Haematologica 2009;94:1762–1766.
- 39.↑
Jaiswal S, Fontanillas P, Flannick J et al.. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371:2488–2498.
- 40.↑
Hicks LK, Bering H, Carson KR et al.. The ASH Choosing Wisely campaign: five hematologic tests and treatments to question. Blood 2013;122:3879–3883.
- 41.↑
Napolitano LM, Kurek S, Luchette FA et al.. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. J Trauma 2009;67:1439–1442.
- 42.
Carson JL, Grossman BJ, Kleinman S et al.. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2012;157:49–58.
- 43.↑
Retter A, Wyncoll D, Pearse R et al.. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol 2013;160:445–464.
- 44.↑
Patton J, Reeves T, Wallace J. Effectiveness of darbepoetin alfa versus epoetin alfa in patients with chemotherapy-induced anemia treated in clinical practice. Oncologist 2004;9:451–458.
- 45.↑
Patton JF, Sullivan T, Mun Y et al.. A retrospective cohort study to assess the impact of therapeutic substitution of darbepoetin alfa for epoetin alfa in anemic patients with myelodysplastic syndrome. J Support Oncol 2005;3:419–426.
- 46.↑
List AF. Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS). Semin Oncol 2005;32:S31–35.
- 47.↑
List A, Dewald G, Bennett J et al.. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006;355:1456–1465.
- 48.↑
Revicki DA, Brandenburg NA, Muus P et al.. Health-related quality of life outcomes of lenalidomide in transfusion-dependent patients with low- or intermediate-1-risk myelodysplastic syndromes with a chromosome 5q deletion: results from a randomized clinical trial. Leuk Res 2013;37:259–265.
- 49.↑
Oliva EN, Latagliata R, Lagana C et al.. Lenalidomide in International Prognostic Scoring System low and intermediate-1 risk myelodysplastic syndromes with del(5q): an Italian phase II trial of health-related quality of life, safety and efficacy. Leuk Lymphoma 2013;54:2458–2465.
- 50.↑
Giagounidis A, Mufti GJ, Mittelman M et al.. Outcomes in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study. Eur J Haematol 2014;93:429–438.
- 51.↑
Goss TF, Szende A, Schaefer C et al.. Cost effectiveness of lenalidomide in the treatment of transfusion-dependent myelodysplastic syndromes in the United States. Cancer Control 2006;13(Suppl):17–25.
- 52.↑
Exjade [prescribing information]. Stein, Switzerland: Novartis Pharma Stein AG; 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_ docs/label/2013/021882s019lbl.pdf. Accessed January 23, 2015.
- 53.↑
Tolley K, Oliver N, Miranda E et al.. Cost effectiveness of deferasirox compared to desferrioxamine in the treatment of iron overload in lower-risk, transfusion-dependent myelodysplastic syndrome patients. J Med Econ 2010;13:559–570.
- 54.↑
Fenaux P, Mufti GJ, Hellstrom-Lindberg E et al.. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10:223–232.
- 55.
Silverman LR, McKenzie DR, Peterson BL et al.. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006;24:3895–3903.
- 56.
Silverman LR, Demakos EP, Peterson BL et al.. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol 2002;20:2429–2440.
- 57.↑
Kantarjian H, Oki Y, Garcia-Manero G et al.. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007;109:52–57.
- 58.↑
Kogan AJ, Dunn JD. Myelodysplastic syndromes: health care management considerations. Manag Care 2009;18:25–28; discussion 28-29.
