Treatment of high or very high risk myelodysplastic syndromes

INTRODUCTION — Myelodysplastic syndromes (MDS) comprise a heterogeneous group of malignant hematopoietic stem cell disorders that are characterized by ineffective blood cell production and a variable risk of transformation to acute myeloid leukemia (AML). (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

This topic will discuss management of patients with high risk (>4.5 to 6 points) and very high risk (>6 points) MDS, according to the revised International Prognostic Scoring System (IPSS-R) (table 1) (calculator 1). (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

The following topics are discussed separately:

●(See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

●(See "Overview of the treatment of myelodysplastic syndromes".)

●(See "Treatment of lower-risk myelodysplastic syndromes (MDS)".)

●(See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately.

●(See "COVID-19: Considerations in patients with cancer".)

GOALS OF CARE — Goals of care for patients with high/very high risk MDS are informed by medical fitness, individual preference, and institutional approach. Age alone does not define the goals of care in this setting. (See 'Stratification by medical fitness' below.)

●For most medically fit patients and for many patients of intermediate medical fitness, the goal is to achieve long-term survival with the possibility of cure.

●For most patients of intermediate fitness or who are medically frail, the primary goals are to alleviate symptoms, improve quality of life, and/or prolong life; some medically fit patients may choose these goals based on age or personal preference.

●For patients with extreme debility, advanced age, or severe comorbid medical conditions, treatment aimed at modifying the disease course may be inadvisable, and supportive care alone should be offered.

Goals of care should be established in discussions between the patient, loved ones, and clinicians at the time of diagnosis, and reassessed periodically through the course of the disease. Mutual understanding of goals of care is important for optimal selection of therapy and facilitates conversations regarding health care proxies, do-not-resuscitate directives, and end-of-life decisions.

INITIAL MANAGEMENT — There is no standard initial treatment for all patients with high/very high risk MDS, and we encourage participation in a clinical trial. Medical fitness, genetic features of the MDS cells, institutional/clinician approach, and patient preference are important factors for selecting treatment, and we suggest referral to transplantation specialists soon after diagnosis to evaluate eligibility for allogeneic hematopoietic stem cell transplantation (HCT) and to define donor options; age alone should not be an exclusion for this evaluation. (See 'Evaluation of fitness' below and "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Some patients with high/very high risk MDS are free of symptoms at the time of diagnosis, and it may be reasonable to elect a period of observation to assess the trajectory of the disease and/or to defer treatment. However, most patients are symptomatic with anemia, thrombocytopenia, and/or recurrent infections. Supportive care for symptoms associated with MDS (eg, transfusions, erythropoiesis stimulating agents, antibiotic therapy) is discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

Management of special populations of patients is discussed below. (See 'Special patient populations' below.)

STRATIFICATION BY MEDICAL FITNESS

Evaluation of fitness — We suggest evaluation of medical fitness, including performance status, physiologic fitness, and cognition in a manner similar to that for older patients with acute myeloid leukemia, as described separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Pretreatment evaluation'.)

Soon after diagnosing high/very high risk MDS, patients who are medically fit or of intermediate fitness should be referred to transplantation specialists to evaluate eligibility for allogeneic hematopoietic cell transplantation (HCT) and to define donor options. Age alone should not be an exclusion for this evaluation. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

For some patients, it may be helpful to obtain geriatric consultation and/or perform a more comprehensive functional assessment to evaluate medical fitness, as presented separately. (See "Comprehensive geriatric assessment for patients with cancer".)

Medically fit — There is no consensus regarding optimal management of the medically fit patient with high/very high risk MDS. A broad range of treatment options exists, and choices vary based on clinician/institutional approach, goals of care, and personal preference. Medical fitness, rather than age alone, should inform the selection of therapy. Other important factors for selecting treatment are availability of a suitable stem cell donor and/or caregiver and genetic features of the MDS cells (algorithm 1), as described below. (See 'Options for suitable patients' below.)

Most medically fit patients are eligible for intensive treatments, such as allogeneic HCT and/or remission induction chemotherapy; these approaches have the potential to achieve long-term disease-free survival, but they are associated with substantial short-term and long-term toxicity. Some patients may instead choose lower intensity therapy with hypomethylating agents, which cause less toxicity and can provide relief of symptoms, improve the quality of life, and extend survival; however, these agents do not have the potential to cure MDS. For patients with particular genetic features, treatment with a targeted agent may be an option, but the role and long-term outcomes with such agents for MDS are presently uncertain. Certain medically fit patients may select supportive care alone based on goals of care, personal preference, advanced age, or lack of an available caregiver.

Intermediate fitness — Intermediate medical fitness comprises a broad range of patients, some of whom have only modest, recent, or transient impairment of functional status, while others have substantial comorbid illnesses, cognitive impairment, or other conditions that may affect their ability to tolerate treatment.

Some patients of intermediate fitness are suitable for intensive treatment (eg, allogeneic HCT or remission induction therapy), but comorbidities may affect the balance of benefits versus toxicity and/or may influence eligibility. Selection of treatment for patients of intermediate fitness depends on institutional approach, goals of care and personal preference, availability of a stem cell donor and/or caregiver, and genetic features of the MDS cells. Geriatric consultation and evaluation by transplantation specialists may be valuable for determining whether a patient of intermediate medical fitness is a suitable candidate for intensive treatment. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

For patients who are candidates for intensive therapy, our approach is described below. (See 'Patients suitable for intensive treatment' below.)

For patients who are not suitable for intensive therapy, we favor participation in a clinical trial or other approaches, as described below. (See 'Not suitable for intensive treatment' below.)

Medically frail — Care of medically frail patients is focused primarily on relieving symptoms and improving the quality of life. Selection of therapy is informed by the individual's preferences and goals of care. (See 'Goals of care' above.)

●Supportive care should be offered to all medically frail patients. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

●Some medically frail patients may choose to undergo lower intensity treatment for symptom relief and/or improved quality of life. (See 'Lower intensity treatment' below.)

PATIENTS SUITABLE FOR INTENSIVE TREATMENT

Options for suitable patients — There is no consensus regarding optimal treatment for patients who are candidates for intensive treatment (eg, transplantation or intensive remission induction chemotherapy). However, soon after the diagnosis of high/very high risk MDS is established, the patient should be referred to transplantation specialists to evaluate eligibility for allogeneic hematopoietic cell transplantation (HCT). Age alone should not preclude this evaluation. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Treatment selection is influenced by pathologic features (eg, the presence of adverse or targetable genetic features), availability of a suitable stem cell donor and caregiver, patient preference, and institutional approach (algorithm 1). Treatment options involve different levels of treatment intensity and toxicity, so decisions must carefully weigh the balance of benefits and risk in alignment of the individual patient's goals of care. (See 'Goals of care' above.)

Because of a variety of stem cell donor options (eg, siblings, unrelated donors, haploidentical donors, umbilical cord blood donors), a suitable match can be found for most patients. Eligibility criteria for allogeneic HCT vary by institution but, in general, patients should have normal cardiac, pulmonary, liver, and renal function, and Eastern Cooperative Oncology Group (ECOG) performance status ≤2, as described separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'Impact of individual factors'.)

Some patients who are suitable for intensive therapy may select supportive care alone, based on personal preference or goals of care. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

Adverse genetic features — MDS with certain adverse cytogenetic findings (eg, monosomy 7, del 7q, ≥3 chromosomal abnormalities) or particular mutations (eg, TP53) is generally associated with inferior clinical outcomes. For patients with adverse genetic features, we suggest treatment with either allogeneic HCT or lower intensity therapy with a hypomethylating agent (HMA) (algorithm 1), rather than intensive remission induction therapy. Treatment choices are influenced by the specific genetic features, comorbidities, patient preference, and institutional approach.

In this setting, allogeneic HCT offers the possibility of long-term disease control but may cause acute and/or chronic graft-versus-host disease (GVHD), infections, and other toxicity. HMAs are associated with less toxicity than either transplantation or intensive chemotherapy and can control symptoms, enhance the quality of life, and improve cytopenias, but do not offer the possibility of cure. In the setting of adverse genetic features, intensive remission induction therapy alone does not achieve high rates of durable disease control, yet is associated with substantial toxicity.

Either azacitidine or decitabine is acceptable for most patients. However, if an HMA is selected for treatment of MDS with mutant TP53, some experts favor decitabine over azacitidine, as described below. (See 'Hypomethylating agents' below.)

Targetable genetic features — For patients with mutant IDH1 or IDH2, we suggest ivosidenib or enasidenib, respectively, rather than allogeneic HCT, intensive remission induction therapy, or an HMA (algorithm 1). Although there is presently only limited direct evidence of the benefit of these agents for MDS, this suggestion is based on their favorable balance of toxicity and efficacy for relapsed/refractory acute myeloid leukemia (AML).

Ivosidenib and enasidenib are inhibitors of mutant forms of IDH1 and IDH2, respectively, and each is approved by the US Food and Drug Administration (FDA) for treatment of relapsed or refractory AML in patients with mutations of these genes [1,2]. We consider them to be acceptable options for off-label treatment of MDS with mutation of IDH1 or IDH2, based on results with AML. However, the role of these agents for MDS is not well defined, and it is unclear if they can achieve long-term disease control. Because of this, suitable patients who have major responses to these agents should be considered for allogeneic HCT while in remission. These agents are generally well tolerated, but each is associated with a risk of differentiation syndrome. Use of ivosidenib and enasidenib for treatment of relapsed or refractory AML and differentiation syndrome are discussed separately. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction' and "Differentiation syndrome associated with treatment of acute leukemia".)

High/very high risk MDS shares biologic features and aspects of management with AML, and ongoing development of targeted agents for AML will likely alter the therapeutic options for MDS in the future. An overview of AML therapy is described separately. (See "Acute myeloid leukemia in adults: Overview".)

No adverse or targetable genetic features — For patients who do not have the adverse genetic findings or targetable features described above, acceptable therapeutic options include allogeneic HCT, intensive remission induction therapy, or treatment with an HMA (algorithm 1). In this setting, treatment selection is strongly influenced by patient preference/goals of care, and institutional approach:

●Allogeneic HCT provides the highest likelihood of long-term survival and the possibility of cure, but this must be balanced against substantial short-term and long-term toxicity, including infections and acute and/or chronic GVHD. (See 'Allogeneic HCT' below.)

●Some patients may select intensive remission induction chemotherapy, thereby retaining the possibility of long-term disease control while avoiding acute and chronic GVHD and other toxicities associated with allogeneic transplantation. Induction therapy generally utilizes chemotherapy regimens that are used for AML, which are associated with substantial toxicity. (See 'Intensive chemotherapy' below.)

●Treatment with an HMA can provide symptom control, enhanced quality of life, and improved cytopenias, and is associated with modest toxicity, but does not offer the possibility of cure. (See 'Hypomethylating agents' below.)

NOT SUITABLE FOR INTENSIVE TREATMENT — For patients who are not candidates for intensive treatment (eg, based on level of medical fitness, comorbidities, personal preference, institutional approach, no available caregiver, and/or no suitable stem cell donor), we favor participation in a clinical trial.

Other acceptable options include:

●For most patients, we suggest lower intensity treatment with a hypomethylating agent (HMA) rather than supportive care alone, based on the favorable balance of outcomes versus modest toxicity. (See 'Lower intensity treatment' below.)

●A patient with a mutation of IDH1 or IDH2 might choose off-label treatment with ivosidenib or enasidenib, based on their efficacy in AML. (See 'Other lower intensity treatments' below.)

●Some patients may choose supportive care alone, based on individual goals of care or advanced age. Patients with high or very high risk MDS have an estimated median survival of 8 to 18 months with supportive care alone [3]. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

TREATMENT MODALITIES — The approach to treatment is influenced by goals of care and medical fitness, as described above. (See 'Goals of care' above and 'Stratification by medical fitness' above.)

Selection of a particular modality depends on the individual's suitability for intensive treatment (algorithm 1) and other factors that are described in the sections above. (See 'Patients suitable for intensive treatment' above and 'Not suitable for intensive treatment' above.)

All patients should also receive supportive care for relief of symptoms, as described separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

Allogeneic HCT

Selection of allogeneic transplant — Allogeneic hematopoietic cell transplantation (HCT) provides the highest likelihood of long-term survival for the patient with high/very high risk MDS and it is the only approach that offers a substantial possibility of cure. Efficacy of transplantation results from the conditioning chemotherapy plus a graft-versus-tumor (GVT) effect from allogeneic immune reconstitution. However, allogeneic HCT also causes graft-versus-host disease (GVHD) and substantial treatment-related mortality (TRM), with a higher risk of opportunistic infections and chronic cytopenias.

Large cooperative group studies and single institution studies report 30 to 52 percent overall survival (OS), 16 to 50 percent disease-free survival (DFS), and 10 to 50 percent TRM at three years after allogeneic HCT for MDS [4-9]. There is no clear association between age and clinical outcome following allogeneic HCT in studies that included patients with high/very high risk MDS [10-14].

No randomized clinical trials have directly compared allogeneic HCT versus intensive remission induction therapy or other approaches for patients with high/very high risk MDS. However, a Markov decision analysis that included 223 patients ≥60 years old with high/very high risk MDS reported that, compared with lower intensity therapy (azacitidine or decitabine), reduced intensity conditioning allogeneic HCT achieved superior median life expectancy (36 versus 28 months, respectively) and quality-adjusted life expectancy (QALE) [15]. Other retrospective and population-based studies also report that, compared with lower intensity treatment, allogeneic HCT is associated with superior clinical outcomes [7,16,17].

Timing/treatment prior to transplant — There is controversy about whether to proceed to directly to allogeneic HCT versus cytoreductive ("bridging") therapy to reduce the burden of disease prior to transplantation. No randomized trials have directly compared these strategies. However, meta-analyses concluded that for patients with high/very high risk MDS, early allogeneic HCT is associated with maximal life expectancy and superior quality of life, when compared with bridging therapy prior to transplantation [15,18].

For most patients with high/very high risk MDS, we suggest proceeding directly to transplantation. However, we consider cytoreductive bridging therapy as an acceptable alternative in the following settings (algorithm 1):

●If identification of a donor is expected to be delayed (eg, ≥2 to 3 months)

●For patients with circulating blasts or a bone marrow blast count ≥10 percent, especially if they will not receive a myeloablative preparative regimen (eg, for patients >65 years old)

Some experts favor routinely treating patients prior to transplantation to reduce bone marrow blast count. However, there is no definitive evidence of a survival benefit for patients who receive cytoreductive therapy prior to allogeneic HCT. The only randomized trial that attempted to address that issue was stopped early because of slow accrual [5], and most retrospective single institution studies were inconclusive and/or did not account for selection bias [16,19]. Although a higher burden of disease at the time of transplantation is associated with inferior outcomes [20], it is not clear if cytoreductive treatment can alter outcomes or if a higher blast count simply reflects the biology of the MDS. Furthermore, toxicity related to pretransplant therapy could delay or preclude transplantation, or lessen the chance of a successful outcome.

There is no consensus regarding an optimal cytoreductive regimen and the choice of agent is informed by genetic features of the MDS cells, individual preferences, and institutional approach (algorithm 1). Acceptable choices include:

●A hypomethylating agent (HMA; eg, azacitidine or decitabine) (see 'Hypomethylating agents' below)

●Intensive remission induction therapy for patients without TP53 mutation and/or adverse cytogenetic features (see 'Adverse genetic features' above and 'Intensive chemotherapy' below)

●IDH inhibitor (eg, ivosidenib or enasidenib for patients with a known mutation of IDH1 or IDH2, respectively) (see 'Other lower intensity treatments' below)

No particular cytoreductive bridging therapy has been shown to achieve superior outcomes following transplantation. However, a retrospective study of bridging therapy reported that, compared with intensive chemotherapy, treatment with azacitidine achieved a comparable rate of post-transplant relapse, but caused less toxicity [21]. In another study, outcomes were comparable whether pretransplant bridging therapy was azacitidine alone, intensive remission induction therapy alone, or azacitidine followed by intensive remission induction therapy [22]. Other studies reported that survival after allogeneic HCT was comparable whether patients proceeded directly to transplantation or received intensive remission induction therapy prior to allogeneic HCT [23,24].

Donor stem cell source — Institutional preferences, experience, and outcomes may influence the choice of donor source. Based on the favorable balance of clinical outcomes and toxicity, we favor either a matched related donor (MRD; ie, HLA-matched sibling) or matched unrelated donor (MUD; ie, matched at 8 of 8 or 10 of 10 HLA loci). For MRD donors, either peripheral blood or bone marrow are acceptable sources. For MUD grafts, we favor bone marrow over peripheral blood because of less long-term toxicity [25]. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

A multicenter study of 701 adults (median age 53 years) with MDS compared outcomes with MRD (176 patients), MUD (8 of 8 allele-matched; 413 patients), or mismatched MUD (mMUD; ie, 7 of 8 allele-matched; 112 patients) grafts [4]. Recipients of MRD and 8 of 8 MUD grafts had similar DFS and OS at three years, but both were superior to recipients of 7 of 8 allele-matched mMUD grafts. Acute GVHD was higher with MUD grafts than MRD, but rates of chronic GVHD were similar in all three cohorts by three years.

For older transplant recipients, who are more likely to have older siblings for donors, we simultaneously perform sibling testing and search for an MUD. Younger donors are generally preferred because of the lesser chance of having clonal hematopoiesis of indeterminate potential (CHIP) in donors; although it is not yet standard practice, some centers evaluate older potential donors for the presence of CHIP. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis" and "Donor selection for hematopoietic cell transplantation", section on 'Age, sex, and parity'.)

There is less experience with alternative donor sources in this setting, but grafts from haploidentical family members and umbilical cord blood may achieve similar outcomes and are also acceptable donor options. Studies that evaluated various donor sources for allogeneic HCT in MDS have yielded inconsistent and/or inconclusive results [10,26-28]. Alternative graft sources, including mMUD donors, haploidentical family members, or umbilical cord blood are discussed separately. (See "Donor selection for hematopoietic cell transplantation".)

There is no evidence to support the use of autologous HCT for patients with MDS. As an example, in one study, autologous HCT was not superior to intensive chemotherapy alone [29].

Preparative regimen — There is no standard preparative (conditioning) regimen for allogeneic HCT in this setting, and clinical practice varies between institutions. (See "Preparative regimens for hematopoietic cell transplantation".)

Patient age informs the choice of preparative regimen:

●Myeloablative conditioning (MAC) should generally be reserved for patients ≤65 years old

●Reduced intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning are preferred for patients >65 years old

For younger patients, MAC is considered superior to RIC, based on a multicenter study that randomly assigned patients ≤65 years old to MAC versus RIC, which was halted early because RIC was associated with a higher rate of relapse, but only a modest decrease in TRM; OS did not differ significantly between the conditioning regimens [30].

Genetic features may influence outcomes following MAC versus RIC regimens. As an example, mutations of TP53, JAK2, or RAS pathway genes were associated with inferior outcomes, compared with patients who lacked those mutations [31]. A retrospective study of 1514 patients of all ages reported that, compared with patients with TP53 mutation alone, outcomes for patients with TP53 mutation and complex karyotype had particularly poor outcomes [32].

Intensive chemotherapy

Selection of intensive remission induction chemotherapy — The role of high intensity remission induction chemotherapy for high/very high risk MDS is controversial. Such treatment is associated with substantial toxicity and, although it can achieve complete remission (CR) in some patients, responses are generally short-lived unless followed by post-remission allogeneic HCT or consolidation chemotherapy.

There is no consensus regarding the optimal remission induction chemotherapy regimen in this setting. Remission induction regimens are similar to those used for acute myeloid leukemia (AML). Examples include infusional cytarabine plus an anthracycline (eg, so-called "7+3" therapy, which may be modified based on age, medical fitness, and cytogenetic/molecular features), or CPX-351 (liposomal daunorubicin-cytarabine). Regimens that are appropriate for high/very high risk MDS and treatment-related toxicity are discussed separately. (See "Acute myeloid leukemia in adults: Overview", section on 'Intensive remission induction' and "Acute myeloid leukemia: Induction therapy in medically fit adults".)

Outside of a clinical trial, we generally consider intensive remission induction chemotherapy to be an acceptable option for patients with high/very high risk MDS who have all of the following features:

●Patients who are medically fit or of intermediate fitness (see 'Stratification by medical fitness' above)

●Circulating blasts or bone marrow blast count ≥10 percent

●No adverse genetic features, as described above (see 'Adverse genetic features' above)

No randomized studies have directly compared intensive remission induction chemotherapy alone versus either transplantation or lower intensity therapy in this setting. However, outcomes following intensive chemotherapy alone appear inferior to those of allogeneic HCT.

Intensive chemotherapy alone for higher risk MDS achieves CR in more than one-half of patients, but remission generally lasts <12 months and four-year OS is between 8 and 33 percent [23,33-40]. As an example, one multicenter prospective study reported four-year OS and DFS of 15 and 11 percent, respectively, in patients ≤55 years old who underwent remission induction chemotherapy followed by two cycles of cytarabine consolidation (because they had no suitable stem cell donor) [34]. In that study, clinical outcomes with consolidation chemotherapy were inferior to those with allogeneic HCT, but were equivalent to autologous HCT.

Although another multicenter study reported that 15 percent of 184 patients died during remission induction therapy with cytarabine, etoposide, and idarubicin, despite age <60 years (median 47 years) and good performance status [41]. However, TRM has declined substantially since the time of that report, and is closer to 1 to 5 percent with contemporary approaches [42].

Post-remission management — Bone marrow examination should be performed at the time of hematopoietic recovery from induction therapy. We suggest evaluating measurable residual disease (MRD), if the patient has MDS with a molecular feature that permits monitoring of MRD by polymerase chain reaction (PCR) or multiparameter flow cytometry, as discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Introduction'.)

For patients who achieve CR (and have no MRD, if assessed) (algorithm 1), we suggest either allogeneic HCT (for suitable candidates) or consolidation chemotherapy, rather than monitoring alone, as discussed separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Favorable-risk disease'.)

If CR is not achieved or MRD is detected (algorithm 1), treatment options include allogeneic HCT or treatment with an HMA or targeted therapy (based on the specific molecular features), as described separately. (See "Treatment of relapsed or refractory acute myeloid leukemia".)

Lower intensity treatment

Selection of lower intensity therapies — Lower intensity treatments for high/very high risk MDS include HMAs and targeted therapies. A benefit has not been demonstrated for other lower intensity agents (eg, low dose cytarabine) in the setting of high/very high risk MDS. Lower intensity agents generally are associated with modest toxicity, but HMAs offer little opportunity for long-term disease control, and the curative potential of targeted therapies for MDS is presently undefined.

Hypomethylating agents — Azacitidine and decitabine can relieve symptoms, improve the quality of life, and prolong survival in association with modest toxicity. Compared with high intensity chemotherapy or best supportive care, azacitidine and decitabine offer a more favorable balance of outcomes and toxicity for most patients who are not candidates for allogeneic HCT.

Azacitidine and decitabine have not been directly compared with each other in a randomized trial in this setting. Compared with supportive care, azacitidine has a demonstrated survival advantage, but such a benefit has not been proven for decitabine. Some clinicians and/or patients prefer azacitidine because it can be administered subcutaneously as an outpatient (although administration may be painful or cause bruising in thrombocytopenic patients), while others prefer decitabine because of its intravenous route of administration (which may be convenient for patients who have venous access devices). For patients with TP53 mutation, some clinicians specifically favor decitabine because of its efficacy in that setting, as described below [43]. For patients with other genetic features, either azacitidine or decitabine is acceptable and are generally considered equally efficacious. An oral preparation of decitabine combined with cedazuridine (a cytidine deaminase inhibitor) that has been approved by the US Food and Drug Administration (FDA) for treatment of MDS [44] is discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Decitabine'.)

There is no consensus regarding the optimal schedules and doses for HMAs. Optimal duration of therapy is not fully defined, but either azacitidine or decitabine should be given for ≥4 cycles to adequately assess response (algorithm 1); for patients who show a clinical benefit, treatment may be continued indefinitely as maintenance therapy, until resistance or intolerance develops. Further details of treatment with HMAs are presented separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Hypomethylating agents'.)

Examples of informative studies of hypomethylating agents for high/very high risk MDS include:

●Azacitidine – Treatment with azacitidine (median of six cycles) achieved 17 percent CR plus partial response (PR), hematologic improvement in an additional 21 percent, 14 month median survival, and 17 percent estimated three-year survival in a multicenter study of 282 patients, most of whom had higher risk MDS [45,46].

In an international study, 358 patients with higher risk MDS were randomly assigned to either azacitidine (75 mg/m² per day for seven days every 28 days) versus conventional care (selected by the investigator before randomization): best supportive care (145 patients), low dose cytarabine (45 patients), or high intensity AML induction chemotherapy (17 patients) [29]. When compared with conventional care, azacitidine was associated with superior median OS (25 versus 15 months; HR 0.58; 95% CI 0.43-0.77) and two-year OS (51 versus 26 percent), yet less toxicity (eg, grade 3/4 cytopenias and length of hospitalization) [47]. The survival benefit for azacitidine was seen in all prognostic subgroups (ie, poor, intermediate, and favorable cytogenetics) and age groups, including those ≥75 years old [48].

●Decitabine – In a phase III EORTC/German MDS trial of 233 patients with higher risk MDS, compared with best supportive care, decitabine therapy was associated with higher progression-free survival (6.6 versus 3.0 months, respectively) and improved patient-reported quality of life measures, but no difference in OS [49].

A single center phase II study of decitabine (20 mg/m² for 10 consecutive days) was conducted in 116 patients with transfusion-dependent MDS (26 patients), AML (≥60 years old; 54 patients), or relapsed AML (36 patients) [43]. Response rates were higher in patients with TP53 mutation (100 percent of 21 patients) or unfavorable cytogenetics (67 percent of 43 patients) than in patients with intermediate or favorable risk cytogenetics (34 percent) and wild-type TP53 (41 percent). Maximum clinical response required at least two, and often three or four, treatment cycles.

Some experts treat high/very high risk MDS with venetoclax (BCL2 inhibitor) plus an HMA, based on favorable outcomes in preliminary reports in AML [50,51]. Addition of other agents (eg, lenalidomide, vorinostat) to HMAs does not appear to improve outcomes in higher risk MDS [29,52-54].

Other lower intensity treatments — No other agents that are approved for treatment of MDS have a demonstrated role in this setting. However, ivosidenib and enasidenib are inhibitors of mutant forms of IDH1 and IDH2, respectively, and each is approved by the FDA for treatment of relapsed or refractory AML in patients with the corresponding mutations [1,2]. Both agents are well tolerated and are acceptable options for off-label treatment of MDS in patients with an IDH1/2 mutation. Outcomes with these agents for treatment of MDS are not well defined, and it is unclear if they can achieve long-term disease control. Use of these agents for treatment of relapsed AML is discussed separately. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction'.)

Low dose cytarabine does not have a clearly defined benefit in the setting of higher risk MDS. In one study, low dose cytarabine (10 mg/m² subcutaneously twice daily for 21 consecutive days as an outpatient) was superior to best supportive care; cytarabine was associated with a 32 percent response rate, six month median duration of response, and decreased transfusion requirement, but there was a higher rate of infections and no difference in OS or time to progression [55].

SPECIAL PATIENT POPULATIONS — Certain patient populations require modification of the approach described above.

Therapy-related MDS — Therapy-related myelodysplastic syndrome (t-MDS) is a clinical syndrome that arises as a late complication of cytotoxic chemotherapy and/or radiation therapy [56]. Patients with t-MDS comprise a heterogeneous group who have a shorter median survival than patients with de novo MDS. Epidemiology, clinical presentation, and diagnosis of t-MDS are described separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

Treatment of t-MDS is informed by the patient's performance status and medical fitness, and by genetic features, as discussed separately. (See "Therapy-related myeloid neoplasms: Management and prognosis", section on 'Management approach'.)

Patients with 5q deletion — For patients with high/very high risk MDS associated with del(5q), we suggest treatment similar to that of other patients with high/very high risk MDS.

Although lenalidomide achieves excellent outcomes for patients with lower risk MDS associated with del(5q), it is less effective in the setting of high/very high risk MDS with del(5q). As an example, in a phase II trial of 47 patients with high/very high risk MDS with del(5q), lenalidomide (10 mg/day orally) resulted in 27 percent hematologic response (including 15 percent complete hematologic response), but median overall survival was only nine months [57]. Six of nine patients with isolated del(5q) achieved complete remission versus 1 of 11 with one additional chromosomal abnormality and none of those with more than one additional abnormality. Complete remissions were obtained in 35 percent of those with initial platelet counts >100,000/microL versus none of the 27 with platelet counts <100,000/microL.

Use of lenalidomide for lower risk categories of MDS with del(5q) is described separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Chromosome 5q deletion'.)

Chronic myelomonocytic leukemia — Chronic myelomonocytic leukemia (CMML) has elements of both a myelodysplastic and a myeloproliferative disorder. Management of CMML is discussed separately. (See "Chronic myelomonocytic leukemia: Management and prognosis", section on 'Pretreatment evaluation'.)

PATIENT FOLLOW-UP — Patients should be followed longitudinally to assess response to therapy and to monitor for disease progression. Standardized response criteria, based on bone marrow and peripheral blood, are described separately. (See "Overview of the treatment of myelodysplastic syndromes", section on 'Response assessment and monitoring'.)

TREATMENT OF RECURRENT OR REFRACTORY DISEASE — There is a general lack of effective treatments for the management of recurrent or refractory MDS. Patients should be encouraged to participate in clinical trials whenever available.

Outside of a clinical trial, the management of patients with recurrent or refractory MDS is largely dependent on the patient's prior therapy. Examples include:

●Patients who relapse after allogeneic HCT may be candidates for repeat transplantation or donor lymphocyte infusion, as discussed separately. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)'.)

●Patients who have not yet received azacitidine or decitabine (ie, initial treatment was with allogeneic transplantation, high intensity chemotherapy, or targeted therapy) may be offered a trial of azacitidine or decitabine. There is a paucity of data regarding the use of a decitabine after failure of azacitidine or vice versa. (See 'Lower intensity treatment' above.)

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov). For interested patients, relatives, and physicians, the Aplastic Anemia and MDS International Foundation maintains a website (www.aamds.org), which contains additional information as well as a listing of clinical trials in this disorder [58]. (See "Overview of the treatment of myelodysplastic syndromes", section on 'Clinical trials'.)

SOCIETY GUIDELINE LINKS — Our approach is similar to those proposed by the MDS Panel for Practice Guidelines of the National Comprehensive Cancer Network (NCCN), the American Society for Blood and Marrow Transplantation (ASBMT), and the European LeukemiaNet [59-61]. Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myelodysplastic syndromes".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Myelodysplastic syndromes (MDS) (The Basics)" and "Patient education: Allogeneic bone marrow transplant (The Basics)")

●Beyond the Basics topics (see "Patient education: Myelodysplastic syndromes (MDS) in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The revised International Prognostic Scoring System (IPSS-R) calculator is used to categorize patients with high (>4.5 to 6 points) or very high (>6 points) risk myelodysplastic syndromes (MDS) (table 1) (calculator 1). Other prognostic scoring systems for MDS are described separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

●Goals of care for patients with high/very high risk MDS are informed by medical fitness, individual preferences, and institutional approach; age alone does not define the goals of care. (See 'Goals of care' above.)

●There is no standard initial treatment for all patients with high/very high risk MDS, and approaches vary by institution. However, virtually all patients are symptomatic at the time of diagnosis and require prompt supportive care (eg, transfusion support for symptomatic anemia or thrombocytopenia, antibiotic therapy for infection). (See 'Initial management' above.)

Treatment is stratified according to medical fitness, including performance status, physiologic fitness, and cognition, in a manner similar to that for older patients with acute myeloid leukemia (AML), as described separately. Patients who are medically fit or of intermediate fitness should be evaluated by transplantation specialists soon after diagnosis to determine their suitability for allogeneic hematopoietic cell transplantation (HCT) and stem cell donor options. (See 'Stratification by medical fitness' above and "Acute myeloid leukemia: Management of medically unfit adults", section on 'Pretreatment evaluation'.)

●Suitable for intensive treatment – For patients who are suitable for intensive treatments (eg, allogeneic HCT or intensive remission induction therapy), we suggest stratifying treatment according to genetic features of the MDS (algorithm 1):

•Adverse genetic features – For patients with monosomy 7, del 7q, ≥3 chromosomal abnormalities, or mutation of TP53, we suggest either allogeneic HCT or a hypomethylating agent (HMA; eg, azacitidine or decitabine) (algorithm 1), rather than intensive remission induction therapy alone or supportive care alone (Grade 2B). The choice of therapy is determined by patient preference, medical comorbidities, specific genetic features, and institutional approach. (See 'Adverse genetic features' above.)

•Targetable genetic features – For patients with mutant IDH1 or IDH2, we suggest ivosidenib or enasidenib, respectively, rather than allogeneic HCT, intensive remission induction therapy, or an HMA (Grade 2C) (algorithm 1). Although there is presently only limited direct evidence of the benefit of these agents for MDS, this suggestion is based on the favorable balance of toxicity and efficacy for relapsed/refractory AML. (See 'Targetable genetic features' above.)

•For patients with none of the adverse or targetable genetic features described above, acceptable options include allogeneic HCT, intensive remission induction therapy, or treatment with an HMA (algorithm 1), and treatment selection is influenced by eligibility for transplantation (ie, availability of a suitable stem cell donor and caregiver), medical comorbidities, personal preference, and institutional approach. (See 'No adverse or targetable genetic features' above.)

For high/very high risk MDS, allogeneic HCT offers the greatest potential for long-term disease control, but may cause substantial short- and long-term toxicity. HMAs are associated with less toxicity than either transplantation or intensive chemotherapy and can provide symptomatic improvement but do not offer the possibility of cure. High intensity chemotherapy is associated with substantial toxicity and can achieve complete remission in some patients, but responses are generally short-lived unless followed by post-remission allogeneic HCT or consolidation chemotherapy; however, treatment of MDS with adverse genetic features using intensive remission induction therapy does not offer a favorable balance of outcomes and toxicity. Some patients may select supportive care alone based on goals of care or personal preference.

●Not suitable for intensive treatment – For patients who are not candidates for intensive treatment, care should be focused on relieving symptoms and improving the quality of life. Treatment choice is strongly influenced by the level of medical fitness, comorbidities, personal preference, and institutional approach. For such patients, we favor participation in a clinical trial.

Outside of a clinical trial, we suggest lower intensity treatment (eg, azacitidine, decitabine, or targeted therapy) rather than high intensity chemotherapy because of the more favorable balance of outcomes versus toxicity (Grade 2B). (See 'Lower intensity treatment' above.)

●Patients with recurrent or refractory higher risk MDS should be encouraged to participate in clinical trials. Outside of a clinical trial, the management of patients with recurrent or refractory MDS is largely dependent on the patient's prior therapy. (See 'Treatment of recurrent or refractory disease' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Elihu H Estey, MD, who contributed as an author for this topic review.

The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.