Management of Patients with Lower-Risk Myelodysplastic Neoplasms

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1		Karen W.L. Yee	--	3448	2023-07-17 04:22:10	\|
2	format change	Peter Tang	Meta information modification	3448	2023-07-18 04:15:10	\|

This entry is adapted from the peer-reviewed paper 10.3390/curroncol30070459

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal hematologic disorders characterized by morphologic dysplasia, ineffective hematopoiesis, and cytopenia. These three developments allow for more tailored therapeutic decision-making in view of the expanding treatment options in MDS. For patients with lower risk MDS, treatment is aimed at improving cytopenias, usually anemia. The approval of luspatercept and decitabine/cedazuridine have added on to the current armamentarium of erythropoietic stimulating agents and lenalidomide (for MDS with isolated deletion 5q). Several newer agents are being evaluated in phase 3 clinical trials for this group of patients, such as imetelstat and oral azacitidine.

myelodysplastic neoplasm prognostic scoring system lenalidomide luspatercept antithymocyte globulin hypomethylating agent imetelstat

1. Introduction

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal hematologic disorders characterized by morphologic dysplasia, ineffective hematopoiesis, and cytopenias. With recent updates to classification and prognostic systems, alongside improvements in treatment, therapeutic strategies will become more personalized in the coming years.

2. Classifications

Two updated classifications of myeloid malignancies were introduced in 2022: (a) the 5th edition of the World Health Organization classification (WHO 2022) and (b) the International Consensus Classification (ICC 2022). Both continue to expand the disease types that are genetically defined (Table 1) ^[1]^[2]^[3]. The classifications attempt to further refine and subtype this heterogeneous disease. WHO 2022 introduced the term myelodysplastic neoplasm (abbreviated MDS) to replace myelodysplastic syndrome, to emphasize the neoplastic nature of the disease ^[1]^[2]. MDS entities are grouped into those having defining genetic abnormalities and those that are morphologically defined, allowing utilization of more comprehensive risk stratification schemes, such as the Revised International Prognostic Scoring System (IPSS-R), for improved prognostication. A consistent definition of cytopenia is used in both MDS and clonal cytopenia of undetermined significance (CCUS) and the threshold for dysplasia is maintained at 10%. Unlike in the WHO 2016 classification, WHO 2022 does not recognize certain cytogenetic abnormalities being MDS-defining, in the absence of morphologic dysplasia ^[4]^[5]^[6]. The distinction between single lineage (SLD) and multi-lineage dysplasia (MLD) is now considered optional. Hypoplastic MDS (MDS-h) is recognized as a new distinct subtype. The term MDS-excess blasts (MDS-EB) has been replaced by MDS-increased blasts (MDS-IB) compared to MDS-low blasts (<5% blasts; MDS-LB) for better clarification, while maintaining the long-standing cutoff of 10% to distinguish MDS-IB1 and MDS-IB2. This differs from ICC 2022 where MDS-EB2 has been changed to MDS/acute myeloid leukemia (AML) with 10–19% blasts. WHO 2022 softens the boundaries between MDS and AML, but the 20% blast cut-off is retained. WHO 2022 is concerned that (a) lowering the blast cut-off is arbitrary and does not reflect the biologic continuity in myeloid pathogenesis; (b) blast enumeration is subjective and prone to sampling variations/error; (c) no gold standard exists for blast enumeration; and (d) there is a risk of overtreatment if the blast count is lowered. However, there is broad agreement that MDS-IB2 may be regarded as AML-equivalent for therapeutic consideration and clinical trial design.

Table 1. Changes in MDS (Myelodysplastic Neoplasms) Classification.

WHO 2016 (4th ed)	WHO 2022 (5th ed)	ICC 2022
MDS with single lineage dysplasia (MDS-SLD)	MDS with defining genetic abnormalities MDS with low blasts & isolated 5q deletion (MDS-5q) MDS with low blasts & SF3B1 mutation (MDS-SF3B1) ^a MDS with biallelic TP53 inactivation (MDS-biTP53)	MDS with mutated SF3B1
MDS with multilineage dysplasia (MDS-MLD)		MDS with del(5q)
MDS with ring sideroblasts (MDS-RS) MDS-RS-SLD MDS-RS-MLD		MDS with mutated TP53
MDS with isolated del(5q)		MDS, not otherwise specified (MDS, NOS) MDS, NOS without dysplasia MDS, NOS with single lineage dysplasia MDS, NOS with multilineage dysplasia
MDS with excess blasts (MDS-EB) MDS-EB-1 MDS-EB-2	MDS, morphologically defined MDS with low blasts (MDS-LB) MDS, hypoplastic (MDS-h) MDS with increased blasts (MDS-IB) MDS-IB1 MDS-IB2 MDS with fibrosis (MDS-f)	MDS with excess blasts
MDS, unclassifiable (MDS-U)		MDS/AML ^b MDS/AML with mutated TP53 MDS/AML with myelodysplasia-related gene mutations MDS/AML with myelodysplasia-related cytogenetic abnormalities MDS/AML, NOS

ICC—International Consensus Classification; WHO—World Health Organization. ^a Detection of ≥15% ring sideroblasts may substitute for SF3B1 mutation (in cases with wildtype SF3B1 and >15% ring sideroblasts). Acceptable related terminology: MDS with low blasts and ring sideroblasts; ^b the previous category of MDS-EB2 with >10% blasts is changed to MDS/AML, defined as a cytopenic myeloid neoplasm and 10% to 19% blasts in the blood or BM.

ICC 2022 also maintains the threshold of dysplasia at 10%, with a higher threshold being warranted when dysmegakaryopoeisis, other than micromegakaryocytes, are included ^[3]. Similar to WHO 2022, the definition of cytopenia is consistent in MDS and CCUS. ICC 2022 recognizes the following MDS-defining cytogenetic abnormalities, irrespective of dysplasia, in the context of persistent cytopenia: del(5q), multi-hit TP53 mutation, and −7/del(7q) and complex karyotype (>3 unrelated clonal chromosomal abnormalities in the absence of other class-defining recurring genetic abnormalities), which are classified as MDS with del(5q), MDS with mutated TP53, or MDS, not otherwise specified (MDS, NOS), respectively. In the absence of clonality, the diagnosis of MDS requires the presence of qualifying dysplasia and persistent cytopenia.

Both WHO 2022 and ICC 2022 recognize 3 subtypes with MDS-defining genetic abnormalities:

(a) MDS with del(5q), whose definition has not changed, but thrombocytosis (platelet > 450 × 10⁹/L) is permitted.

(b) MDS-SF3B1 is a distinct disease that includes >90% of MDS cases with ≥5% ring sideroblasts (RS). WHO 2022 includes cases with SF3B1 wildtype and RS > 15% in this category to allow inclusion of driver mutations in other RNA splicing components. Patients with low blasts and ≥15% RS without SF3B1 mutation account for 3–4% of all MDS cases. In contrast, ICC 2022 excludes cases without SF3B1 mutation in this category as SF3B1-unmutated MDS-RS cases have clinical features and outcomes similar to MDS with SLD or MLD and are now classified as MDS, NOS, irrespective of the number of RS.

(c) MDS with biallelic (or multihit) TP53 alterations (MDS-biTP53) consists of cases with >2 mutations of TP53 or a TP53 mutation with concurrent TP53 copy loss or copy neutral loss of heterozygosity (e.g., deletion of the other allele on chromosome 17p). TP53 alterations are biallelic in about two-thirds of MDS cases with TP53 alterations. Over 90% of MDS-biTP53 have complex cytogenetics and regarded as very high risk. Some data suggests that MDS-biTP53 may be regarded as an AML-equivalent ^[7]^[8].

3. Risk Assessment

MDS subtypes exhibit different rates of leukemia transformation and overall survival (OS). Prognostic scores are essential tools to predict risk of progression to AML and long-term outcomes (Table 2). Treatment decisions are largely guided by these prognostic risk scores. The IPSS was the first important standard used in determining prognosis for untreated patients with MDS ^[9]. In 2012, the IPSS-R demonstrated improved predictive power by refining marrow blast categories and depth of the cytopenias and allocated more weight to cytogenetic abnormalities ^[10]. However, both the IPSS and IPSS-R were developed using the French-American-British (FAB) classification, which utilized morphology and immunohistochemistry to define disease sub-types, and using data from treatment-naïve patients. Both scores do not include patients with therapy-related and secondary MDS or other genetic changes which affect outcome. These limitations may contribute, in part, to the large heterogeneity in outcomes observed within the IPSS-R intermediate-risk category ^[11]^[12]. Furthermore, both are not dynamic scoring systems.

Table 2. Comparison of MDS Prognostic Scoring Systems.

	IPSS (Greenberg 1997) ^[9]	IPSS-R (Greenberg 2012) ^[10]	IPSS-M (Bernard 2022) ^[13]
Includes CMML	Yes ^a (if WBC ≤ 12 × 10⁹/L)	Yes ^b (if WBC ≤ 12 × 10⁹/L)	Yes ^c (if WBC < 13 × 10⁹/L)
Includes secondary/therapy-related MDS	No	No	Yes ^d
Includes previously treated patients	No	No	Yes
Sensitivity to degree of cytopenias	Limited	Anemia, thrombocytopenia & neutropenia	Anemia & thrombocytopenia ^e
Range of karyotypes	3 categories	5 categories	5 categories
Marrow blasts	<30% ^a	<30% ^b	<20%
Includes gene mutations	No	No	Yes (31)
Number of prognostic variables	3	5	5 ^f
Number of risk groups	4	5	4

^a Including 15% CMML and 8% FAB RAEB-T (AML with 20–30% blasts by WHO classification); ^b Including 9% CMML and 6% FAB RAEB-T (AML with 20–30% blasts by WHO classification); ^c Including 9.5% CMML and 3% MDS/MPN-RS-T and MDS/MPN-U; ^d 8% were secondary/therapy-related; ^e ANC had a small weight in the IPSS-R model but was not independently prognostic in the IPSS-M model; ^f the 31 genes are counted as one variable.

The recently published Molecular IPSS (IPSS-M) was developed using the WHO classification and incorporated hematologic parameters, the IPSS-R cytogenetic risk groups, as well as 31 somatic gene mutations ^[13]. In the discovery cohort, 3% of patients had DDX41 mutations, of which 87% likely had a germline variant, and 30% received treatment (62% hypomethylating agents [HMAs]; 7% intensive chemotherapy; 20% lenalidomide; 30% hematopoietic stem cell transplantation [HCT]). Of the genetic mutations included, multihit TP53, FLT3-ITD and FLT3-TKD, and MLL partial tandem duplication (PTD) were the top predictors of adverse outcome. In contrast, SF3B1 mutations were associated with favorable outcomes, but this was modulated by patterns of co-mutations. The IPSS-M demonstrated improved prognostic accuracy for OS, leukemia free survival (LFS) and AML transformation. The IPSS-M re-stratified 46% of patients in the IPSS-R categories (74% were upstaged and 26% were downstaged). It is applicable for patients with secondary or therapy-related MDS. Additionally, calculation of the IPSS-M allows for missing values with IPSS-M scores generated under the best, average and worst scenarios. Hence, if a significant number of values are missing, there can be a wide range in assigned risk groups and outcomes. Most studies have used the IPSS and IPSS-R to risk stratify MDS patients for inclusion. The IPSS-M is currently undergoing validation.

4. Myeloid Malignancies with Germline Predisposition

Myeloid neoplasms with germline predisposition were first recognized as an entity in the WHO 2016 classification ^[4] and is retained in both WHO 2022 and ICC 2022 ^[1]^[3]. Both classifications recognize that there are other germline variants that predispose individuals to hematologic malignancies (such as CHEK2, Nijmegen breakage syndrome, and CSF3R) that are not included in the current subcategories ^[1]^[3]^[14]. In individuals with genetic conditions associated with an increased risk of hematologic malignancies, myeloid neoplasms with identified germline predispositions can occur. The frequency of pathogenic/likely pathogenic (P/LP) germline variants in MDS patients diagnosed at age < 40 years is 15–20% ^[15]^[16]. In MDS patients of all ages treated with allogeneic HCT, P/LP germline variants were found in 7% ^[17].

With the more widespread use of next generation sequencing (NGS), there is an increasing awareness that individuals may harbor a pathogenic germline mutation that predisposed them to the hematologic malignancy. Accurate identification of patients with germline predisposition disorder is important as it affects management (donor selection for allogeneic HCT, choice of conditioning regimen, and use of post-transplant cyclophosphamide), genetic counseling and surveillance for the affected individual and their family ^[18]^[19].

Universal germline predisposition testing in patients with myeloid neoplasms, regardless of age, is currently not standard of care. Guidelines focus on early identification of younger patients with myeloid neoplasms through personal and family history screening questions, as well as the identification of variants with germline potential on NGS gene panels ^[18]^[19]^[20]^[21]. There are limitations to testing only patients diagnosed with a myeloid neoplasm before the age of 40 or 50 years and/or with a strong personal or family history, as patients may be unaware of their family history and there can be a wide variation in the age of disease onset due to variable penetrance of the germline mutation (e.g., patho-genic DDX41 variants). Furthermore, although somatic NGS panels can detect gene variants that are suspicious for germline alterations, the genes being evaluated in institutional and/or commercial panels may not include all the genes or gene regions involved in germline predisposition disorders, copy number variants are not routinely tested, and there may be technical difficulties, such as with read depth ^[18]^[19].

5. Therapeutic Options

Treatment of LR MDS focuses on improving cytopenias to prevent complications and maintain quality of life (QoL). In patients with untreated LR MDS, death has been attributed to infections (38%), transformation to AML (15%) and bleeding (13%) ^[22]. Isolated neutropenia or thrombocytopenia is uncommon and is more commonly observed in more than one lineage ^[23]^[24]^[25]. Neutropenia is seen in nearly 50% of newly diagnosed patients with MDS, including 15–20% of LR MDS patients. In terms of the use of prophylactic granulocyte colony-stimulating factor (G-CSF), a Cochrane systematic review demonstrated a substantial lack of data for the prevention of infections, prolongation of survival and improvement in QoL ^[26]. However, G-CSF has been used transiently in patients with <5% marrow blasts who have significant infections.

The prevalence of thrombocytopenia in MDS patients ranges from 40% to 65% with severe thrombocytopenia (<20 × 10⁹/L) occurring in <20% of patients ^[25]. In patients with untreated LR MDS, 51% and 12% of patients had platelet counts <100 × 10⁹/L and <20 × 10⁹/L, respectively, compared with 77% and 29%, respectively, in those with HR MDS. Two thrombopoietin (TPO) receptor agonists (i.e., romiplostim and eltrombopag) have been evaluated in MDS patients. Romiplostim was evaluated in randomized, placebo-controlled, phase 2 study in patients with LR MDS and thrombocytopenia ^[27]^[28]. Although romiplostim did not reduce the incidence of clinically significant bleeding events (p = 0.13), protocol-defined platelet transfusions were significantly reduced (p < 0.0001) and platelet responses were also higher in the romiplostim arm (36.5% vs. 3.6%, p < 0.001). The study was terminated because of concerns that the transient increases in peripheral blasts observed with romiplostim put patients at risk for progression to AML. Five-year follow-up for transformation to AML and death did not differ between the 2 groups ^[29]. A subsequent trial of romiplostim in LR MDS with <5% marrow blasts demonstrated a hematologic improvement-platelet response (HI-P) rate of 42% with a median response duration of 48.5 weeks ^[30]. Predictors of response were SRSF2 mutation status and base-line hemoglobin levels, but not endogenous TPO levels or platelet transfusion history.

Eltrombopag has also been assessed in a randomized, placebo-controlled, single blinded study in patients with LR MDS and thrombocytopenia ^[28]. Higher platelet responses (42.3% vs. 11.1%, p < 0.001) and decreased bleeding events (19.8% vs. 31.5%, p = 0.0002) were observed in the eltrombopag arm compared to placebo. There was no difference in AML transformation between the 2 groups (9% vs. 7%, p = 0.729). Both agents are approved in the United States (US), Canada and Europe for the treatment of chronic immune thrombocytopenia and in the case of eltrombopag, for severe aplastic anemia, but they are not approved for the treatment of thrombocytopenia in patients with LR MDS. However, both romiplostim and eltrombopag have been used off label to increase platelet counts and decrease bleeding events in patients with LR MDS with <5% blasts.

Anemia is the most common cytopenia in MDS patients, with >80% of patients being anemic at diagnosis ^[23]^[31]^[32]. Red blood cell (RBC) transfusions are the cornerstone of best supportive care (BSC). However, it is associated with iron overload which can affect organ function ^[33]^[34]^[35], transfusion reactions, and decrease in QoL, thus warranting the use of other therapeutic options (as discussed below). The medications for MDS patients have been approved based on studies defining LR MDS as IPSS low and intermediate-1 risk and/or IPSS-R very low, low and intermediate-risk (with some studies including IPSS-R scores of 4 to 4.5) (Table 3; Figure 1).

Figure 1. Drug Approval Timelines.

Table 3. Drug approvals for Lower-risk MDS.

Drug	Indication	Regulatory Status	Reference
Azacitidine (AZA)	for the treatment of patients with the following [FAB] MDS subtypes: refractory anemia or refractory anemia with ring sideroblasts (if accompanied by neutropenia or thrombocytopenia and requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia (CMML)	FDA (2004)	Silverman 2002; Kornblith 2002; Silverman 2006 ^[36]^[37]^[38]
Azacitidine (AZA)	for the treatment of adult patients with (a) IPSS Intermediate-2 and High-risk MDS and (b) AML with 20–30% blasts and multi-lineage dysplasia, according to the WHO classification ^a,b	FDA (expanded 2008); EMA (2008); HC (2009)	Fenaux 2009 ^[39]
Lenalidomide (LEN)	for the treatment of transfusion-dependent anemia in patients with IPSS Low or Intermediate-1 risk MDS with chromosome 5q deletion ^c	FDA (Sub-part H 2005); EMA (2013); HC (2008)	Fenaux 2011 ^[40]
Deferasirox (DFX)	for use in treating chronic iron overload due to transfusional hemosiderosis in patients ≥ 2 years of age	FDA (2005); EMA (2006)	Shashaty 2006; Cappellini 2006; Cappellini 2011 ^[41]^[42]^[43]
Deferasirox (DFX)	for the management of chronic iron overload in patients with transfusion-dependent anemias aged ≥6 years and in patients aged 2 to 5 who cannot be adequately treated with deferoxamine	HC (2006)
Decitabine (DEC)	for the treatment of adult patients with de novo or secondary MDS, untreated or previously treated with chemotherapy, including the following: (a) IPSS Intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System (IPSS) groups and (b) all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and CMML) ^a	FDA (2006); HC (2019)	Kantarjian 2006 ^[44]
Decitabine/cedazuridine (DEC-C)	for the treatment of adult patients with de novo or secondary MDS, untreated or previously treated with chemotherapy, including the following: (a) IPSS Intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System (IPSS) groups and (b) all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and CMML)	FDA (2020); HC (2020)	Garcia-Manero 2019; Savona 2021 ^[45]^[46]
Luspatercept	for the treatment of anemia failing an ESA and requiring ≥2 RBC units over 8 weeks in adult patients with [IPSS-R] very low- to intermediate-risk MDS with ring sideroblasts (MDS-RS) ^d	FDA (2020); EMA (2020); HC (2021)	Fenaux 2020 ^[47]

EMA—European Medicine Agencies; FDA—US Food and Drug Administration; HC—Health Canada. ^a HC approval only if patients are not considered candidates for HCT; ^b EMA approval only if patients are not considered candidates for HCT; ^c EMA approval only when other therapeutic options are insufficient or inadequate; ^d FDA approval also for patients with myelodysplastic/myeloproliferative neo-plasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

6. Newer Agents in Later Stages of Development

6.1. Imetelstat

Imetelstat is a 13-mer oligonucleotide targeting the RNA template of human telomerase. It is a first in-class competitive inhibitor of telomerase enzymatic activity. High telomerase activity has been seen in MDS and imetelstat targets cells with active telomerase. A phase 2/3 study (MDS3001) evaluating imetelstat in LR MDS patients who are relapsed/refractory or ineligible for ESAs is ongoing (NCT02598661). Data from the phase 2 part of this study have been reported ^[48]. Patients could not have received prior HMA or LEN. The 8- and 24-week RBC TI rate in the overall population was 37% and 23%, respectively, with median TI duration of 65 weeks. HI-E rate was 65% with a 63% reduction in RBC transfusion burden from baseline. A higher proportion of patients with >50% reduction in expression of human telomerase reverse transcription (hTERT) achieved 8-week RBC TI. The most common adverse events were reversible cytopenias. Among responders, attainment of 24-week TI was predictive of a likelihood to achieve TI of more than 1 year ^[48]^[49].

Preliminary results of the randomized, placebo-controlled phase 3 portion of the trial were announced on 4 January 2023 (NCT02598661) ^[50]. The trial met its primary and secondary endpoints with improved 8-week RBC TI (39.8% vs. 15%, p < 0.001) and 24-week RBC TI (28% vs. 3.3%, p < 0.001) in patients receiving imetelstat compared to placebo, respectively. Median 8-week RBC TI duration approached 1 year for imetelstat compared to approximately 13 weeks for placebo (p < 0.001, HR = 0.23). Median 24-week RBC TI duration approached 1.5 years for imetelstat. RBC TI was achieved across all subtypes including those patients having RS and high or very high transfusion burden. The company is planning to submit for FDA approval in 2023.

6.2. Roxadustat

Roxadustat is an orally active and reversible inhibitor of hypoxia inducible factor prolyl hydroxylase (HIF-PH) ^[51]^[52]. Roxadustat thus prevents hydroxylation of HIF-α allowing for the transcription and expression of genes necessary for erythropoiesis. The open-label, dose selection, lead-in stage of the randomized phase 3, double-blind, placebo-controlled trial evaluating the efficacy and safety of roxadustat compared with placebo in red cell transfusion-dependent IPSS-R very low, low, and intermediate risk MDS has completed enrolment (NCT03263091) ^[53]. The lead-in stage was performed to determine the recommended phase 3 dose (RP3D) to be used for the phase 3 portion of the study. Forty-two percent of patients enrolled were ESA-naive and 58% of patients were ESA relapsed or refractory. RBC TI was achieved in 9 patients (37.5%) at 28 and 52 weeks. It was well tolerated with no fatalities or progression to AML. Roxadustat 2.5 mg/kg was chosen as the RP3D. The primary endpoint of the phase 3 portion of the study is RBC TI for >8 weeks. Enrolment has been completed; however, results have not been reported.

7. Treatment Algorithm for Lower-Risk MDS

All patients should receive supportive care based on symptoms, including RBC and platelet transfusions, G-CSF (if septic and/or recurrent severe infections), and antimicrobials as indicated (Figure 2). If the patient has progressed to a higher risk category, the patient should be transitioned to therapeutic options for HR MDS.

Figure 2. Lower Risk MDS: Treatment Algorithm.

If eligible and available, all patients should be considered for a clinical trial as there is an ongoing need to improve outcomes. Patients with biallelic TP53 mutations have a poor outcome with no effective therapies. The phase 3 trial of AZA with or without eprenetapopt in mono- and bi-allelic TP53 mutated MDS failed to meet its primary endpoint of CR rate with no difference in OS ^[54].

With increasing therapeutic options for patients with LR MDS, optimal sequencing of therapy needs to be addressed. Most of the studies that have led to drug approval have excluded patients who received prior therapy with LEN and HMAs. Retrospective studies suggest that the use of LEN before a HMA might be a better strategy than the reverse order ^[55]^[56]. Similarly, response to luspatercept after exposure to HMAs and LEN is lower than in patients who did not receive prior HMAs and/or LEN ^[57].

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