Risk-Stratified Treatment Strategies for Lower-Risk MDS

In the management of patients with myelodysplastic syndrome (MDS), the decision to initiate therapy must account for the complexities of disease biology, risk assessment, and patient-centered treatment goals. An important part of the discussion is ensuring the patient understands the severity of the disease, which may be underestimated at diagnosis, and that realistic outcomes are communicated to appropriately align goals of both the patient and physician.1,2 The conversation should then proceed to an assessment of the patient’s individual risk, since an accurate estimate of prognosis informs decisions about timing and choice of treatment.

The Revised International Prognostic Scoring System (IPSS-R) is the emerging gold standard for risk stratification.3 Using the IPSS-R, clinicians divide MDS into higher-risk (IPSS-R >4.0) and lower-risk disease (IPSS-R ≤4.0),4 of which patients can be further stratified into very low-risk (IPSS-R ≤1.5), low-risk (IPSS-R >1.5–3), intermediate-risk (IPSS-R >3–4.5), high-risk (IPSS-R >4.5–6), or very high-risk (IPSS-R >6). These risk categories are instrumental in prognosticating patients and estimating the risk of evolution to acute myeloid leukemia (AML).5 Its use can be facilitated through online calculators (http://advanced.ipss-r.com)5 and applications for mobile devices.6

Overall survival (OS) varies widely among the risk groups. Based on the IPSS-R, in the absence of therapy, the median OS is 8.8 years for very low-risk patients and 5.3 years for low-risk patients, compared to 3 years for intermediate-risk, 1.6 years for high-risk and <1 year for very high-risk patients.6 In contrast to higher-risk disease, where the aim is to modify the disease course and prolong survival, the major goals of therapy for lower-risk disease are hematologic improvement with minimal use of transfusions, management of symptoms, and optimization of quality of life.3,4,7

Defining Lower-Risk MDS

In stratifying by risk, the IPSS-R considers percentage of marrow blasts, baseline depth of cytopenias, sixteen separate cytogenetic abnormalities, and five cytogenetic subgroups, along with various other differentiating features, such as age, performance status, serum ferritin, lactate dehydrogenase, and beta-2-microglobulin.6

A low blast percentage (<5%), favorable cytogenetics, and normal karyotype or del(5q) alone, del(20q) alone, or –Y alone are other good-prognosis features and are associated with prolonged survival. Requirement for RBC transfusions is a negative prognostic factor for patients in the lower-risk MDS groups.4

Age is a more significant prognostic factor among lower-risk than higher-risk groups,3 and treatment-related MDS, which may occur due to prior anti-cancer therapy with agents such as chemotherapy and radiation, tends to convey worse survival than primary MDS of unknown cause.8 Somatic mutations are being explored for their clinical and prognostic implications, but are not yet clinically applicable. In the future, some genetic profiles may signal more aggressive disease and the need to initiate treatment sooner rather than later.

Treatment of Lower-Risk MDS

Especially in the elderly, managing MDS can be complicated by the patient’s comorbidities and other age-related factors, including intolerance to intensive therapy. Clinicians should address the relevant quality of life domains, including physical, functional, emotional, spiritual and social, which can adversely affect patients.4

The decision to initiate therapy in lower-risk MDS is largely based on the presence of symptomatic anemia and/or compromised quality of life. Symptomatic anemia has been defined as the need for two or more units of packed red blood (pRBC) cells per 28 days and the inability to maintain eight consecutive weeks without RBC transfusions in a 16-week period.9 For patients with anemia, transfusion or RBC growth factors (erythropoiesis-stimulating agents, ESAs) are often given first, unless there is rapid progression. Treatment goals for lower-risk patients should focus on minimizing RBC transfusions and optimizing quality of life.

Since no single treatment approach has yielded an improvement in OS in asymptomatic patients with relatively preserved blood cell counts, observation (with monitoring of blood cell counts at least every 6 months) is acceptable.7 In all cases, the various aspects of supportive care should be considered, including clinical monitoring, psychosocial support, assessment of quality of life, and cytopenia-related complications that require intervention (See NCCN Guidelines Version 1.2017 page MDS-7).

Risk-Stratified Treatment Selection in MDS

Even within the lower-risk category of patients, risk can be stratified and treatment given accordingly for patients with clinically significant cytopenias4:

  • Symptomatic anemia and del(5q) chromosomal abnormality: treat with lenalidomide
  • Symptomatic anemia with serum epoetin ≤500 mU/mL: treat with recombinant human erythropoietin or darbepoetin, with or without granulocyte colony stimulating factor
  • Symptomatic anemia and serum epoetin >500 mU/mL with good probability of responding to immunosuppressive therapy: treat with anti-thymocyte globulin (ATG) or cyclosporine
  • Symptomatic anemia and serum epoetin >500 mU/mL with poor probability of responding to immunosuppressive therapy: treat with azacytidine, decitabine, or lenalidomide
  • Patients with other serious cytopenias: consider azacytidine or decitabine, or enrollment on clinical trial

A simple algorithm for lower-risk MDS was provided by Sekeres and Gerds in the 2014 Educational Book of the American Society of Hematology.7 When a patient is managed as lower risk but fails to respond, the NCCN recommends moving the patient to a higher-risk management strategy.6

(Enlarge Figure)

Managing Anemia in MDS
Treatment of anemia or symptomatic disease is often successful with blood transfusions or erythropoietic stimulating agents (ESAs). This includes RBC for symptomatic anemia, and platelet transfusions for thrombocytopenic bleeding. Aminocaproic acid or other antifibrinolytic agents may be considered for bleeding refractory to platelet transfusions or profound thrombocytopenia.4

The recommendation from the NCCN is to limit transfusions to the minimal number of units necessary to relieve symptoms or restore normal hemoglobin levels, which supports Choosing Wisely®, the American Board of Internal Medicine (ABIM) campaign to reduce wasteful or unnecessary treatments or procedures.10 Iron overload occurs in patients requiring relatively large quantities of RBC transfusions, resulting in adverse effects on hepatic, cardiac, and endocrine function. Patients should be monitored for toxicities in these organ systems, such as abdominal pain and signs of cirrhosis, arrhythmias and signs of heart failure, or adrenal and signs of diabetes mellitus.4

To address the potential for iron overload, the NCCN guidelines recommend that iron chelation drugs be considered in subsets of lower-risk patients, such as those who receive >20 RBC transfusions. Specifically, the NCCN recommends that clinicians consider giving deferoxamine subcutaneously or deferasirox/ICL670 orally once daily to reduce iron overload in patients with lower-risk disease for whom ongoing RBC transfusions are anticipated, and for patients with serum ferritin levels >2,500 ng/mL, aiming for a target ferritin level <1,000 ng/mL.4 A boxed warning has been issued for deferasirox, related to renal and hepatic failure, primarily in elderly patients with multiple comorbidities. Close monitoring of patients on deferasirox, therefore, is recommended.4

Deferasirox Boxed Warning

Deferasirox may cause:
  • renal impairment, including failure
  • hepatic impairment, including failure
  • gastrointestinal hemorrhage
In some reported cases, these reactions were fatal. These reactions were more frequently observed in patients with advanced age, high risk myelodysplastic syndromes, underlying renal or hepatic impairment or low platelet counts. This therapy requires close patient monitoring, including measurement of serum creatinine and/or creatinine clearance as specified in the PI and serum transaminases and bilirubin as specified in the PI.

ESAs can lead to hematologic improvement lasting two years in about 40% of lower-risk anemic patients.11,12 Patients deemed most likely to respond to ESAs are those with low or absent transfusion requirements and low serum erythropoietin level.13 Darbepoetin alfa is a longer-acting form of erythropoietin that has been shown to produce erythroid responses in 40% to 60% of lower-risk patients,14,15 which may be higher than achieved with epoetin.14-17 Features that predict response have included relatively low basal serum erythropoietin levels, low percentage of marrow blasts, and limited number of prior RBC transfusions.4

While concerns have been raised about the safety of ESAs, studies have shown that they actually improve survival in patients with low-risk MDS and low transfusion needs.18,19 Although not currently FDA-approved for the management of patients with MDS, ESAs are routinely used in practice to prevent or reduce the need for blood transfusions.

Non-responders and patients with del(5q) abnormality may respond best to lenalidomide, which blocks the effects of pro-apoptotic, pro-inflammatory cytokines and is potentially cytotoxic as well.6 In clinical trials, lenalidomide resulted in transfusion independence at 24 weeks in 66% of lower-risk MDS patients with del(5q), and responses were durable beyond two years.20,21 Patients on lenalidomide are at risk for generally transient neutropenia and/or thrombocytopenia, therefore, blood counts should be closely monitored.4

Lenalidomide can also be considered for the treatment of symptomatically anemic non-del(5q) patients whose anemia does not respond to initial therapy,4 and is currently under investigation in clinical trials. In a phase 3, multicenter, randomized, double-blind, placebo-controlled study (NCT01029262), lenalidomide is being investigated in patients with low or intermediate-1 risk MDS without del(5q); the primary endpoint is the percentage of patients who achieve RBC transfusion-independence for ≥56 days.

Managing Thrombocytopenia in MDS
Patients with isolated thrombocytopenia (<20,000/L or <50,000/L with bleeding) can start thrombopoietin agonists (on a clinical trial), receive platelet transfusions, or enroll in a clinical trial; non-responders to these options should start a hypomethylating agent (or enroll in a trial).7 A recent placebo-controlled trial found both platelet transfusion dependence and clinically significant bleeding were reduced with romiplostim.22 In another recent randomized phase II trial of low- and intermediate-1 IPSS-risk patients with severe thrombocytopenia, eltrombopag significantly improved platelet counts and fatigue.23

Two experimental drugs targeting transforming growth factor-beta (TGF-β), luspatercept and sotatercept, achieved an erythroid response in about 40% of patients with low- or intermediate-1 risk.24,25 In a phase II study presented at the 2015 American Society of Hematology Annual Meeting, luspatercept produced a sustained increase in hemoglobin levels, and reduced transfusion requirement or transfusion independence in the majority of patients.26

For the patient with multiple cytopenias, recommended treatment options include anti-thymocyte globulin or a hypomethylating agent (or trial enrollment).7

The upfront use of granulocyte (or granulocyte macrophage) colony-stimulating factors for patients with neutropenia has not been shown, in prospective trials, to prevent febrile neutropenia or prolong survival, and is therefore not recommended.7

In the management of patients with MDS, treatment is initiated based on risk of disease evolution, presence of symptoms, comorbidities, and patient preference. A comprehensive assessment of risk will guide most treatment decisions, since outcomes are strongly related to risk group. For patients deemed to have lower-risk disease, the major goals of therapy are hematologic improvement, management of symptoms, and optimization of quality of life. Supportive care includes RBC transfusions or ESAs for symptomatic anemia, and platelet transfusions for severe thrombocytopenia or thrombocytopenic bleeding, and lenalidomide for patients with del(5q) abnormality. A number of experimental agents are in development for treating thrombocytopenia.


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