Myelodysplastic syndromes/neoplasms (MDS): Treatment of higher-risk MDS

INTRODUCTION — Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of malignant hematopoietic stem cell disorders characterized by ineffective blood cell production and a variable risk of transformation to acute myeloid leukemia (AML). MDS and AML are components of a spectrum of myeloid malignancies that share certain aspects of pathophysiology, natural history, and management.

These disorders are called myelodysplastic syndromes in the International Consensus Classification [1] and myelodysplastic neoplasms in the World Health Organization 5^th edition [2]. We refer to them as MDS, while acknowledging minor differences in labels, classification, and diagnostic criteria in the current classification schemes.

We categorize individual cases as higher-risk MDS versus lower-risk MDS according to clinical, cytogenetic, and molecular features. We use the International Prognostic Scoring System-Molecular (IPSS-M) for prognostic classification. The revised IPSS (IPSS-R) (table 1) (calculator 1) is also acceptable for prognostic classification, but the original IPSS is outmoded and should not be used.

The goals of management of MDS are to alleviate symptoms, improve quality of life, and/or prolong survival. Management of higher-risk MDS is individualized according to the patient's suitability for intensive therapy, including allogeneic hematopoietic cell transplantation.

This topic discusses the management of higher-risk MDS.

Related topics include:

●(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".)

OVERVIEW — The outcomes and management of MDS are guided by the prognostic category (ie, higher risk versus lower risk). Determination of the MDS prognostic category is discussed below. (See 'Prognostic category' below.)

Management of higher-risk MDS is individualized, with consideration of age and medical fitness, including eligibility for allogeneic hematopoietic cell transplantation (HCT). Eligibility for allogeneic HCT is discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

We encourage enrollment in a clinical trial, especially in patients who are not eligible for allogeneic HCT.

●Goals – The goals of management for patients with higher-risk MDS are informed by medical fitness and patient preference. Age alone does not define the goals of care in this setting.

•For most medically fit patients, we seek to achieve long-term survival with the possibility of cure.

•For patients who are not candidates for allogenic HCT, the primary goals are to alleviate symptoms, improve quality of life, and/or prolong life.

•For patients with extreme debility, advanced age, or severe comorbidities, supportive care is provided, but treatments to modify the course of disease are generally not possible.

●Symptom management – Most patients with higher-risk MDS have symptoms related to anemia, thrombocytopenia, and/or recurrent infections.

All patients should receive supportive care, such as transfusions, erythropoiesis-stimulating agents, and antibiotics to provide symptomatic relief before and during treatment, as discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Treatments'.)

For patients who are asymptomatic at diagnosis, it may be reasonable to elect a period of observation to assess the trajectory of the disease before initiating treatment.

●Disease-altering treatments – The choice of treatment to alter the disease course is guided by medical fitness, as follows:

•Medically fit for allogeneic HCT (see 'Medically fit patients' below)

•Not suitable for allogeneic HCT (see 'Less-fit patients' below)

PROGNOSTIC CATEGORY — The prognostic category of MDS is best determined with a tool that incorporates clinical, laboratory, cytogenetic, and molecular data.

We use the International Prognostic Scoring System-Molecular (IPSS-M) for determining the prognostic category of MDS [3]. The risk score in IPSS-M can be determined with an online calculator.

If IPSS-M is not available, we consider IPSS-Revised (IPSS-R) (table 1) (calculator 1) acceptable for risk stratification.

The original IPSS should not be used. It is outmoded because it uses only limited clinical and cytogenetic data, does not incorporate molecular findings, and lacks the prognostic accuracy of IPSS-M and IPSS-R. Nevertheless, patients classified as high risk or intermediate-2 according to the original IPSS can be considered to have higher-risk MDS.

We consider higher-risk MDS to include the following IPSS-M or IPSS-R categories:

●IPSS-M (https://mds-risk-model.com/)

•Very high risk

•High risk

•Moderate high risk

●IPSS-R (table 1)

•High risk (4.5 to 6 points)

•Higher risk (>6 points)

•Intermediate risk (>3 to 4.5 points) with TP53 mutation

MDS prognostic models are discussed in detail separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

PRETREATMENT EVALUATION — Pretreatment evaluation of the patient with higher-risk MDS includes assessment of symptoms, comorbid conditions, and eligibility for intensive treatments, including allogeneic hematopoietic cell transplantation (HCT).

Clinical and laboratory testing

●Clinical

•History – Symptoms related to cytopenias (eg, fatigue, infections, bleeding/bruising), transfusion history, comorbid illnesses.

•Physical examination – Signs associated with cytopenias, hepatosplenomegaly.

●Laboratory

•Hematology – Complete blood count with differential, reticulocyte count, review of blood smear.

•Serum chemistry – Comprehensive metabolic panel, lactate dehydrogenase, serum erythropoietin.

•Infectious – Human immunodeficiency virus (HIV) testing.

●Pathology – Bone marrow examination, including morphology, flow cytometry, cytogenetic/molecular testing.

Details of the diagnosis and classification of MDS are discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

Fitness — Medical fitness is judged by the patient's functional, physiologic, and cognitive function. Age, per se, does not determine the fitness category.

Assessment tools — We use the following instruments to assess medical fitness:

●Performance status – Eastern Cooperative Oncology Group (ECOG) scale (table 2)

●Physiologic fitness – Modified Charlson comorbidity index (CCI) (table 3)

The evaluation of performance status, physiologic fitness, and cognition is like that for older patients with acute myeloid leukemia, as described separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Pretreatment evaluation'.)

For some individuals, it may be useful to obtain geriatric consultation and/or perform a more comprehensive functional assessment, as discussed separately. (See "Comprehensive geriatric assessment for patients with cancer".)

Fitness categories — Methods for assessing fitness for allogeneic HCT vary among experts and institutions. In addition to ensuring that there is adequate medical fitness, the patient must have adequate social supports for the various challenges associated with transplantation.

Fitness categories are not rigid, and an individual's fitness can be affected by consequences and complications of MDS itself. We find it useful to periodically reassess fitness because, for some patients, fitness can improve with treatment, while for others, it can decline with adverse effects of therapy.

We apply the following broad fitness categories to individual patients with higher-risk MDS. In assigning a fitness category, we seek to protect patients from treatments that they are unlikely to tolerate, while not depriving patients of the opportunity to achieve remission and prolonged survival.

●Medically fit – Most patients who are medically fit or have only modest functional or physiologic impairment may be eligible for allogeneic HCT. Such patients generally have both of the following:

•ECOG performance status (PS) (table 2): 0 to 2

•Modified CCI (table 3): 0 to 2

We refer medically fit patients <75 years to transplantation specialists to evaluate eligibility for allogeneic HCT and define donor options. Eligibility criteria for allogeneic HCT vary by institution, but patients should have adequate cardiac, pulmonary, liver, and renal function. Eligibility for HCT is discussed in greater detail separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

●Less fit – Significant functional or physiologic impairments (unless disease-related, eg, night sweats, weight loss), which are generally reflected in either of the following:

•ECOG PS: 3

•Modified CCI: ≥3

●Frail – Severe disability and/or comorbid illnesses; examples include:

•ECOG: 3 or 4

•Modified CCI: ≥4

Some experts advocate broadly considering resilience to both disease-related and transplant-related stressors when judging fitness in older patients [4]. With this approach, geriatric assessment using a multidisciplinary team supplements a standard psychosocial evaluation to assess physiologic aging and the social "ecosystem" (which includes caregivers, social support, finance, and other resources).

MEDICALLY FIT PATIENTS — For medically fit patients with higher-risk MDS, we suggest allogeneic hematopoietic cell transplantation (HCT) rather than approaches that don't include transplantation. This suggestion is based on superior survival with allogeneic HCT compared with nontransplant-based approaches, such as intensive induction therapy or hypomethylating agent (HMA)-based treatment.

The decision to pursue transplantation must be individualized. Factors to consider include age, performance status, comorbid conditions, graft availability, a caregiver and adequate psychosocial support, and the patient's values and preferences. Most institutions limit allogeneic HCT to patients <75 years, but age, per se, does not drive this decision. Age is not associated with outcomes in allogeneic HCT for higher-risk MDS, as discussed below. (See 'Prognostic factors' below.)

Allogeneic HCT is associated with substantial short-term and long-term toxicity and some early treatment-related mortality (TRM), but it offers greater potential for long-term disease control/cure than other approaches. No randomized trials have directly compared these approaches for higher-risk MDS.

●A prospective study that used biologic randomization (ie, transplantation if a suitable donor was available) reported that allogeneic HCT was associated with better survival compared with HMA-based therapy or best supportive care (BSC) in patients 50 to 75 years with higher-risk MDS [5]. Patients were assigned to undergo reduced-intensity conditioning (RIC) HCT if a human leukocyte antigen (HLA)-matched donor was identified within 90 days of enrollment. Compared with 124 patients who received HMA-based therapy or BSC, transplantation in 260 patients was associated with a superior three-year overall survival (OS; 48 versus 27 percent; odds ratio [OR] 2.76 [95% CI 1.59-4.81]) and a better three-year leukemia-free survival (36 versus 21 percent; OR 2.28 [95% CI 1.24-4.22]). The survival advantage of transplantation was seen across subgroups, including age (ie, ≤65 versus >65 years).

●RIC HCT was associated with better outcomes than ongoing HMA therapy in a prospective multicenter study [6]. Patients (a median of 63 years) with higher-risk MDS received four to six cycles of azacitidine, and those with a suitable graft donor underwent RIC HCT, while the others continued azacitidine therapy. Two-thirds of 162 patients who began azacitidine treatment were eligible for postinduction therapy assignment; 81 patients underwent RIC HCT, while 27 continued azacitidine treatment. Transplantation was associated with a superior three-year event-free survival (EFS; 34 versus 0 percent) and a trend toward better three-year OS (50 versus 32 percent). One-year cumulative TRM was 19 percent in transplanted patients.

●Markov decision analysis of 223 patients (age 60 to 70 years) with higher-risk MDS reported that, compared with HMA therapy (either azacitidine or decitabine), RIC HCT was associated with superior median life expectancy (36 versus 28 months, respectively) and better quality-adjusted life expectancy [7]. The advantage associated with transplantation held, whether survival was measured from the time of treatment or the time from diagnosis. Another Markov analysis of HCT for higher-risk MDS also concluded that early transplantation in patients with higher-risk MDS was associated with superior survival [8].

●Other retrospective and population-based studies also reported better outcomes with allogeneic HCT than lower-intensity treatments for patients with higher-risk MDS [9-11].

The graft-versus-tumor effect from an allogeneic graft is an important contributor to the benefit of allogeneic HCT in this setting; there is no role for autologous HCT in patients with MDS.

Timing of transplantation — We consider it acceptable to either proceed directly to allogeneic HCT (ie, when a suitable graft is available) or to treat with bridging therapy prior to transplantation.

The approach is individualized, and it may be influenced by the availability of a suitable graft and by pathologic features. Bridging therapy is generally given when obtaining the graft will require ≥2 to 3 months. Some experts favor cytoreductive therapy when there is a heavy disease burden (eg, ≥10 percent blasts in blood or marrow), especially in patients who will not receive myeloablative conditioning (MAC). A higher disease burden at transplantation has been associated with inferior outcomes [12], but it is not clear if pretransplant cytoreductive treatment can alter outcomes, and toxicity related to bridging therapy can potentially delay or preclude transplantation.

The only randomized trial to address the timing of transplantation was stopped early because of slow accrual [13]. Observational studies that addressed the timing of transplantation include:

●In a retrospective study of 165 patients who underwent allogeneic HCT for higher-risk MDS or secondary acute myeloid leukemia (AML), outcomes were similar whether patients received prior cytoreductive therapy [14]. Upfront HCT was performed in 41 percent of patients, 39 percent first received intensive induction chemotherapy, and 21 percent first received HMA therapy; there was no difference in five-year OS (61, 50, and 45 percent, respectively), relapse-free survival (RFS), or nonrelapse mortality (NRM) with the three approaches. Among patients who underwent upfront transplantation, there was no difference in OS or RFS between patients with pretransplant blast count ≥10 percent versus <10 percent.

●Among 139 patients who underwent allogeneic HCT for higher-risk MDS, there was no difference in survival between 28 patients who proceeded directly to allogeneic HCT compared with 111 who received chemotherapy before transplantation [15]. Among patients who were treated with chemotherapy, 39 percent achieved complete remission (CR) prior to HCT.

●Two meta-analyses that used Markov decision analysis concluded that early transplantation maximized life expectancy in patients with higher-stage MDS [7,8].

●Among 131 patients who underwent allogeneic HCT for MDS, longer disease duration prior to allogeneic HCT was associated with inferior OS and disease-free survival (DFS) [16].

Bridging therapy — Selection of a bridging regimen is informed by the patient's fitness and MDS pathologic features.

Bridging therapy options include:

●HMA-based therapy (eg, with or without venetoclax) (see 'Hypomethylating agents' below)

●Intensive chemotherapy (see 'Intensive chemotherapy' below)

No regimen is clearly superior, and the approach varies among experts. No randomized trials have directly compared various bridging therapies. Prospective and retrospective studies of bridging therapy for MDS include:

●A study of 265 patients who underwent allogeneic HCT for MDS reported no significant differences in outcomes according to the type of bridging therapy that was given prior to transplantation [17]. There were no significant differences in three-year OS, relapse, or NRM among patients who received azacitidine (48 patients), intensive chemotherapy (98 patients), or azacitidine plus intensive chemotherapy (17 patients) prior to allogeneic HCT for MDS [17].

●In a retrospective single-institution study, there was no difference in one-year OS, RFS, or NRM between 36 patients who received azacitidine versus 30 who received intensive chemotherapy as bridging therapy prior to allogeneic HCT for MDS [18]. The risk of relapse was lower in patients treated with azacitidine (hazard ratio [HR] 0.34 [95% CI 0.12-0.94]), but the estimated one-year OS did not differ significantly (57 percent with azacitidine, 36 percent with intensive chemotherapy).

●A meta-analysis of 635 patients from 6 studies who underwent allogeneic HCT for MDS reported no difference in OS or RFS according to the use of HMA bridging therapy [19]. However, older patients were more likely than younger patients to receive bridging therapy, and among older patients, the use of an HMA was associated with better survival (HR 0.75 [95% CI 0.57-0.98]).

Other studies have also described the use of HMAs as bridging therapy prior to allogeneic HCT [17,18,20,21]. Importantly, allogeneic HCT should proceed even if bridging therapy does not achieve CR because there was a survival benefit with transplantation even for patients whose MDS did not respond to cytoreductive therapy [5].

A randomized trial comparing HMA versus induction chemotherapy as bridging therapy before allogeneic HCT is ongoing (clinicaltrials.gov NCT01812252).

Conditioning regimen — We stratify the choice of conditioning regimen according to age and medical fitness.

Age ≤65 years — For most patients ≤65 years, we suggest MAC rather than lower-intensity conditioning regimens, based on superior outcomes.

A multicenter study that randomly assigned patients ≤65 years to MAC versus RIC was halted early because RIC was associated with lower OS, more relapses, and only a modest decrease in TRM [22]. Patients with MDS or AML (18 to 65 years) with HCT comorbidity index (HCT-CI) scores ≤4 and <5 percent marrow blasts were randomly assigned to receive MAC (135 patients) versus RIC (137 patients), followed by an HLA-matched related donor or matched unrelated donor graft. Accrual was stopped when interim analysis reported that RIC was associated with a higher rate of relapse (48.3 versus 13.5 percent) and lower TRM (4.4 versus 15.8 percent). Multivariable analysis reported that 18-month OS was higher with MAC (77.5 versus 67.7 percent; HR for mortality 0.64 [95% CI 0.38-0.98]).

We manage transplant-eligible patients with comorbidities that might increase toxicity of HCT, graft-versus-host disease (GVHD), or GVHD prophylaxis like patients >65 years. (See 'Age >65 years or less fit' below.)

Age >65 years or less fit — For patients >65 years or with moderate comorbidities, we suggest RIC or nonmyeloablative (NMA) conditioning rather than MAC. NMA or RIC HCT is associated with more favorable outcomes in older patients and in those with comorbidities that might increase toxicity of MAC HCT.

Transplantation using RIC or NMA conditioning is associated with acceptable outcomes in older patients. The Center for International Blood and Marrow Transplant Research (CIBMTR) reported a 36 percent two-year OS with RIC transplantation for MDS or AML among 1080 patients >40 years (1995 to 2005) [23]. A multicenter study of 148 patients (median age 59 years) who underwent NMA HCT reported a 20 percent three-year OS and 22 percent three-year RFS among 40 patients with de novo MDS [24]. The three-year NRM was 32 percent, and graft rejection occurred in 15 percent among the entire transplanted population.

Studies that compared RIC or NMA versus MAC transplantation in patients with MDS include:

●A multicenter study reported that among 836 patients who were transplanted for MDS, RIC was associated with similar survival rates but less toxicity and more relapses than MAC [25]. Compared with 621 patients who received MAC HCT, the 215 patients who received RIC HCT had a similar OS and progression-free survival (PFS) but a lower three-year NRM (HR 0.61 [95% CI 0.41-0.91]) and higher three-year relapse rate (HR 1.64 [95% CI 1.2-2.2]) [25]. Patients who underwent RIC were older (73 percent >50 years versus 28 percent >50 years) and had more adverse pretransplant features.

●Among 207 adults (50 to 59 years) who were transplanted for hematologic malignancies (one-quarter had MDS), multivariate analysis reported that MAC was associated with an inferior OS compared with RIC (HR 2.57 [95% CI 1.72-3.84]) [26].

●A retrospective single-institution study of HCT in 152 patients >50 years (29 percent with MDS) reported trends toward a higher median OS (13 versus 5.8 months) and median PFS (7.8 versus 4.4 months) with NMA transplantation compared with MAC [27].

Donor source — HLA-matched donors are preferred by most transplantation centers, but the development of alternative donor sources and management of transplant-related toxicity enable the identification of a suitable transplant donor for most transplant-eligible patients.

Either an HLA-matched sibling donor (MSD) or an HLA-matched unrelated donor (MUD; ie, matched at 8 of 8 or 10 of 10 HLA loci) is preferred. For patients without an available MSD or MUD graft, the preference for a haploidentical donor versus an umbilical cord graft varies among institutions.

A multicenter study of 701 adults (median age 53 years) with MDS compared outcomes with MSD (176 patients), MUD (8 of 8 allele matched; 413 patients), or mismatched MUD (mMUD; ie, 7 of 8 allele matched; 112 patients) grafts [28]. The three-year OS and DFS were similar with MSD and MUD grafts, but mMUD grafts were associated with inferior outcomes. Rates of chronic GVHD were similar in all three cohorts, but acute GVHD was higher with MUD compared with MSD grafts.

Although studies using haploidentical and umbilical cord grafts are more limited in this setting, outcomes may approach those with MSD or MUD transplantation [29,30].

Graft source — The choice of bone marrow versus peripheral blood stem/progenitor cell grafts for allogeneic HCT in adults with hematologic malignancies is discussed separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells", section on 'Adults'.)

Prognostic factors — Outcomes of allogeneic HCT for MDS are associated with certain cytogenetic and pathologic features, but age is not independently associated with outcomes.

●Cytogenetics – Outcomes with transplantation are associated with mutated TP53 and other cytogenetic findings.

•Mutations of TP53, JAK2, or RAS pathway genes were associated with inferior outcomes in patients who were transplanted for MDS [31]. The adverse prognostic effect of mutated TP53 was similar whether patients underwent RIC or MAC HCT, whereas in patients with RAS pathway mutations, the risk of relapse was increased in patients who received RIC but not MAC HCT. Compared with unmutated JAK2, patients with JAK2 mutations had a shorter median survival (2.3 versus 0.5 years).

•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].

●Measurable residual disease – Outcomes in patients with detectable measurable residual disease (MRD) may be affected by the type of conditioning regimen.

•A single-institution study reported that outcomes for patients with detectable MRD (by flow cytometry or cytogenetics) at the time of transplantation were associated with conditioning regimen intensity [33]. At transplantation, 23 percent of 287 patients were MRD negative, 53 percent were in CR with detectable MRD, and 24 percent had >5 percent bone marrow blasts. For patients who were MRD negative, and for patients with >5 percent blasts, outcomes were not associated with the intensity of conditioning therapy. However, among 38 patients with cytogenetically detectable MRD, OS was inferior when patients received low-intensity conditioning compared with high-intensity conditioning (HR 7.23 [95% CI 2.38-22]). Among 80 patients who received low-intensity conditioning, cytologically detectable MRD was associated with inferior outcomes, primarily due to increased relapses.

●Age – There is no clear association between age and clinical outcomes with allogeneic HCT in studies that included patients with higher-risk MDS; however, there are few reports of allogeneic HCT in patients ≥75 years.

•Age was not associated with OS, PFS, or NRM in a prospective study of NMA conditioning allogeneic transplant in 372 patients (60 to 75 years) with MDS, AML, and other hematologic malignancies [34].

•Two studies of RIC HCT for MDS reported no association of age with TRM [35,36].

•Age was not associated with NRM, relapse, or GVHD in a multivariate analysis of 1080 patients >40 years who underwent RIC HCT for MDS or AML in first remission [23].

Other studies also reported no association of age with outcomes with allogeneic HCT for higher-risk MDS [37,38].

LESS-FIT PATIENTS — For patients with higher-risk MDS who are not eligible for allogeneic hematopoietic cell transplantation (HCT), we suggest azacitidine-based therapy based on improved overall survival (OS) compared with other approaches.

Subcutaneous azacitidine is the only treatment that is proven to achieve superior OS compared with either supportive care or intensive chemotherapy in patients who are not eligible for allogeneic HCT. Other hypomethylating agent (HMA) regimens (eg, decitabine or alternative methods/schedules of azacitidine administration) are associated with response rates that are comparable to subcutaneous azacitidine, but they have not been proven to provide an OS advantage. Nevertheless, some clinicians and/or patients choose an alternative approach for treatment with an HMA because of convenience or other reasons.

Administration and outcomes with azacitidine and decitabine are discussed below. (See 'Azacitidine' below and 'Decitabine' below.)

●The phase 3 AZA-001 trial randomly assigned 358 patients with higher-risk MDS who were not eligible for allogeneic HCT to subcutaneous azacitidine versus conventional care (either chemotherapy or supportive care) [39]. Compared with conventional care, azacitidine achieved a longer median OS (25 versus 15 months; hazard ratio [HR] 0.58 [95% CI 0.43–0.77]).

●Subsequent analysis of AZA-001 reported that, compared with patients randomly assigned to receive low-dose cytarabine, azacitidine achieved more and longer hematologic responses, more red blood cell transfusion independence, fewer grade ≥3 cytopenias, and shorter hospitalizations [40]. Even in patients who had a hematologic response to azacitidine but did not achieve complete remission or partial respons, azacitidine reduced mortality (HR 0.09 [95% CI 0.06-0.15]) compared with conventional care [41]. The survival benefit for azacitidine was seen in all prognostic subgroups (ie, poor, intermediate, and favorable cytogenetics) and age groups; among the 87 patients ≥75 years, azacitidine achieved a better two-year OS (55 versus 15 percent; HR 0.48 [95% CI 0.26-0.89]) than supportive care [42].

FRAIL PATIENTS — For frail patients, care is focused primarily on relieving symptoms and improving the quality of life.

●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 'Hypomethylating agents' below.)

Patients with higher-risk MDS have an estimated median survival of 8 to 18 months with supportive care alone, but survival outcomes in frail patients are not well defined [43].

TREATMENTS

Hypomethylating agents — The hypomethylating agents (HMAs) azacitidine and decitabine are used to treat higher-risk MDS in patients who are not eligible for allogeneic hematopoietic cell transplantation (HCT). Both agents can provide hematologic responses, symptom relief, and improved quality of life with only modest toxicity, but only azacitidine was proven to prolong overall survival (OS) compared with other approaches in this patient population. (See 'Azacitidine' below.)

Azacitidine and decitabine have not been directly compared in randomized trials. 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 favor decitabine because of its intravenous route of administration, which is convenient for patients with venous access devices. An oral preparation of decitabine combined with cedazuridine (a cytidine deaminase inhibitor) has been approved by the US Food and Drug Administration (FDA) for the treatment of MDS. (See 'Decitabine' below.)

HMAs can also be used as bridging therapy when obtaining a suitable allogeneic graft is prolonged, but the transplant should not be delayed while seeking to achieve a remission, as discussed above. (See 'Bridging therapy' above.)

Azacitidine

●Administration – Azacitidine 75 mg/m²/day subcutaneously for seven days every 28 days. Other schedules can be used, such as subcutaneous azacitidine 75 mg/m²/day for five days, followed by two days of rest, and then two more days of treatment every 28 days ("5-2-2"). Alternate azacitidine protocols are associated with similar response rates as the seven-day subcutaneous schedule, but they have not been proven to improve survival [44,45].

Azacitidine treatment should continue for at least four to six cycles. Most patients in the AZA-001 trial achieved a response by the sixth cycle, but up to one-half of patients required 12 cycles to attain their best response [46].

Azacitidine is approved by the FDA and by the European Medicines Agency (EMA) for the treatment of MDS.

●Toxicity – Azacitidine is associated with cytopenias, kidney toxicity, tumor lysis syndrome, and hepatotoxicity in patients with severe pre-existing liver impairment.

●Outcomes – A randomized trial showed that azacitidine achieved superior OS compared with supportive care or intensive chemotherapy [39], as discussed above. (See 'Less-fit patients' above.)

Response rates using five days of intravenous or subcutaneous azacitidine were similar to those using seven consecutive days of intravenous treatment [44,45], but a survival benefit has not been proven with these protocols.

Decitabine

●Administration – Decitabine 20 mg/m²/day intravenously for five days every four weeks. Treatment should continue for at least four to six cycles.

Decitabine and an oral preparation that combines decitabine 35 mg plus cedazuridine 100 mg are approved by the FDA.

Decitabine is approved by the EMA for the treatment of acute myeloid leukemia (AML), but it is not approved for MDS.

●Toxicity – Decitabine is associated with cytopenias.

●Outcomes – Studies of decitabine for MDS include:

•A phase 3 trial that randomly assigned 233 transplant-ineligible patients ≥60 years with higher-risk MDS to decitabine versus best supportive care reported that decitabine achieved better outcomes [47]. Decitabine 15 mg/m² was given intravenously three times each day for three consecutive days every six weeks. The median OS and AML-free survival did not differ between trial arms, but decitabine achieved superior progression-free survival (PFS; 6.6 versus 3 months; hazard ratio [HR] 0.68 [95% CI 0.52–0.88]), lower risk of progression to AML at one year (22 versus 33 percent), and greater improvement in patient-reported fatigue and physical functioning. Decitabine achieved 13 percent complete remission (CR); 6 percent partial remission (PR); and 15 percent hematologic improvement, compared with 0 percent CR, 0 percent PR, and 2 percent hematologic improvement with supportive care.

•Another phase 3 trial reported that among 170 patients with MDS (two-thirds with higher-risk MDS) who were randomly assigned to decitabine versus supportive care, decitabine achieved more durable responses and reduced the need for transfusions [48]. For the entire trial population, there was a trend toward longer OS with decitabine (12.1 versus 7.8 months); subgroup analysis of the patients with higher-risk MDS reported that decitabine was associated with a longer median time to death or AML (12 versus 6.8 months). Decitabine reduced the need for transfusions and achieved durable responses (median 10.3 months), including 17 percent overall response, 9 percent CR, and 13 percent hematologic improvement. By contrast, there were no hematologic responses among patients who received supportive care alone.

•A trial that randomly assigned three different decitabine regimens for 95 patients with MDS or chronic myelomonocytic leukemia reported best outcomes with 20 mg/m²/day intravenously for five days compared with 20 mg/m²/day subcutaneously for five days or 10 mg/m²/day intravenously for 10 days [49].

•Among 115 patients with higher-risk MDS treated with various decitabine protocols, the median OS was 22 months, overall response rate (ORR) was 70 percent (including 35 percent CR), and median remission duration was 20 months [50]. Other studies also reported good response rates in patients with higher-risk MDS [48,51,52]. Another study reported that one-third of patients experienced cytogenetic conversion with decitabine [21].

•Studies of the combination of oral decitabine plus cedazuridine reported outcomes that are similar to a five-day treatment with intravenous decitabine [53,54].

Other lower-intensity treatments — No other agents that are approved for the treatment of MDS have a demonstrated role in this setting.

●Venetoclax – Some experts treat with an HMA plus venetoclax [55,56], as for the treatment of AML. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'HMA plus venetoclax'.)

●IDH inhibitors – Inhibitors of mutant IDH1 (ivosidenib, olutasidenib) and mutant IDH2 (enasidenib) are used to treat AML, but their efficacy for MDS is not well defined.

Ivosidenib is approved by the FDA for the treatment of newly diagnosed AML with a susceptible IDH1 mutation in adults ≥75 years or with comorbidities that preclude treatment with intensive induction chemotherapy. Because many cases of higher-risk MDS are classified as MDS/AML in the International Consensus Classification [1], ivosidenib may be an option for the treatment of such patients in the United States. The treatment of AML with mutated IDH1 with ivosidenib is discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'IDH inhibitors'.)

Olutasidenib and enasidenib are not approved by the FDA or EMA for the treatment of newly diagnosed MDS or AML.

●Low-dose cytarabine – Low-dose cytarabine does not have a clearly defined benefit for higher-risk MDS. Cytarabine is not approved for the treatment of MDS by the FDA or EMA.

In one study, low-dose cytarabine 10 mg/m² subcutaneously twice daily for 21 consecutive days was superior to best supportive care [57]. 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.

Outcomes with low-dose cytarabine were inferior to those with azacitidine in the AZA-001 trial [40], as discussed above. (See 'Less-fit patients' above.)

Intensive chemotherapy — The role of high-intensity remission induction chemotherapy for higher-risk MDS is controversial.

Intensive induction therapy should only be given to medically fit individuals, and it is associated with substantial toxicity. Although intensive induction therapy is associated with CR in some patients, responses are generally short-lived unless followed by allogeneic HCT or consolidation chemotherapy. There is no consensus regimen, but options are like those used for AML, such as infusional cytarabine plus an anthracycline (eg, so-called "7+3" therapy) or CPX-351 (liposomal daunorubicin-cytarabine). Such regimens 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".)

No randomized trials have directly compared intensive remission induction chemotherapy with other treatments for higher-risk MDS, but intensive chemotherapy was inferior to allogeneic HCT in prospective and retrospective studies, as discussed above. (See 'Medically fit patients' above.)

Intensive chemotherapy alone for higher-risk MDS achieves CR in more than one-half of patients, but remission generally lasts <12 months, and the four-year OS is between 8 and 33 percent [58-66]. As an example, one multicenter prospective study reported a four-year OS and disease-free survival (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) [60]. In that study, clinical outcomes with consolidation chemotherapy were inferior to those with allogeneic HCT, but they were equivalent to autologous HCT.

PATIENT FOLLOW-UP — Patients should be followed longitudinally to assess response to therapy and to monitor for disease progression.

The schedule and protocol for follow-up is individualized. Standardized response criteria in bone marrow, blood, and measurable residual disease have been described [67-69].

Further discussion of response assessment is described separately. (See "Overview of the treatment of myelodysplastic syndromes", section on 'Response assessment and monitoring'.)

RELAPSED OR REFRACTORY DISEASE — Patients should be encouraged to participate in clinical trials whenever available.

The management of patients with relapsed or refractory MDS is guided by prior therapy and fitness.

Examples include:

●Relapse after allogeneic hematopoietic cell transplantation (HCT) – Donor lymphocyte infusion or repeat allogeneic HCT. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)'.)

●No prior hypomethylating agent (HMA) – Azacitidine or decitabine can be used in patients who relapse after allogeneic transplantation or intensive chemotherapy but did not receive an HMA.

●Relapse after HMA – Some experts add venetoclax (BCL2 inhibitor) to an HMA based on favorable outcomes in acute myeloid leukemia (AML) [70,71]. For MDS with mutated IDH1 or IDH2, a targeted agent can be added to an HMA, and gilteritinib may be an option for an acquired mutation of FLT3. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Treatments'.)

There is no evidence that changing the HMA (eg, azacitidine after decitabine failure or vice versa) or adding other agents (eg, lenalidomide, vorinostat) is associated with improved outcomes in higher-risk MDS [39,72-74].

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 [75]. (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 [76-78]. 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

●Description – Myelodysplastic syndromes/neoplasms (MDS) are malignant hematopoietic stem cell disorders characterized by ineffective blood cell production and variable risk of transformation to acute myeloid leukemia (AML). Management is guided by the prognostic category (ie, higher-risk versus lower-risk MDS).

●Higher-risk MDS – We use the International Prognostic Scoring System-Molecular (IPSS-M) for determining the prognostic category. IPSS-M incorporates clinical, laboratory, cytogenetic, and molecular data and can be calculated with an online calculator. (See 'Prognostic category' above.)

IPSS-Revised (table 1) (calculator 1) is also acceptable for MDS risk stratification, but the original IPSS is outmoded, inaccurate, and should not be used.

●Fitness – Judged according to suitability for intensive treatment.

•Assessment tools – Medical fitness is based on performance status (table 2) and physiologic fitness (table 3). (See 'Assessment tools' above.)

•Fitness categories – We categorize patients as:

-Medically fit

-Less fit

-Frail

●Medically fit – For medically fit patients with higher-risk MDS, we suggest allogeneic hematopoietic cell transplantation (HCT) rather than treatments that don't include transplantation (Grade 2B). (See 'Medically fit patients' above.)

Considerations for allogeneic HCT include:

•Timing – Either prompt transplantation (as soon as a suitable graft is available) or bridging therapy prior to transplantation is acceptable. (See 'Timing of transplantation' above.)

•Bridging therapy – There is no consensus regimen for patients who will receive bridging therapy prior to transplantation, but options include treatment with a hypomethylating agent with or without venetoclax or intensive induction therapy. (See 'Bridging therapy' above.)

•Conditioning therapy – Guided by age and fitness:

-≤65 years – For most patients ≤65 years, we suggest myeloablative conditioning (MAC) rather than lower-intensity conditioning regimens (Grade 2B). (See 'Age ≤65 years' above.)

->65 years or less fit – For patients >65 years or with moderate comorbidities, we suggest reduced-intensity conditioning or nonmyeloablative conditioning rather than MAC (Grade 2C). (See 'Age >65 years or less fit' above.)

•Donor – Human leukocyte antigen (HLA)-matched sibling donors or HLA-matched unrelated donors are preferred, but alternative donor sources, such as haploidentical donors or umbilical cord blood donors, are acceptable. (See 'Graft source' above.)

•Graft source – The choice of bone marrow versus peripheral blood stem/progenitor cell grafts is discussed separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells", section on 'Adults'.)

●Less fit – For patients who are not eligible for allogeneic HCT, we suggest azacitidine-based therapy (Grade 1B). (See 'Less-fit patients' above.)

●Frail – For frail patients, care is focused primarily on relieving symptoms and improving the quality of life with supportive care. (See 'Frail patients' above.)

●Relapsed/refractory disease – A clinical trial is strongly encouraged. Other options are guided by prior treatments and medical fitness, as discussed above. (See 'Relapsed or refractory disease' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Elihu H Estey, MD, and Stanley L Schrier, MD, who contributed to earlier versions of this topic review.