Vol 53, No 2 (2022)
Guidelines / Expert consensus
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Treatment recommendations developed by MDS experts of the Polish Adult Leukemia Group (PALG) for management of myelodysplastic syndromes (MDSs) and other MDS-related conditions in Poland for 2021

Krzysztof Mądry1, Bożena Katarzyna Budziszewska2, Karol Lis1, Joanna Drozd-Sokołowska1, Bartłomiej Pogłódek3, Rafał Machowicz1, Edyta Subocz4, Katarzyna Wisniewska-Piąty5, Tomasz Wróbel6, Jan Maciej Zaucha7, Ewa Zarzycka7, Ewa Karakulska-Prystupiuk1, Lidia Gil8, Aleksandra Butrym9, Agnieszka Tomaszewska1, Grzegorz Władysław Basak1, Anna Waszczuk-Gajda1, Agnieszka Pluta10, Paweł Szwedyk11, Małgorzata Jarmuż-Szymczak8, Jagoda Rytel1, Jadwiga Dwilewicz-Trojaczek1
Acta Haematol Pol 2022;53(2):75-93.

Abstract

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 into acute myeloid leukemia. In recent years, significant progress in MDS biological research has allowed the addition of new drugs to the few existing therapeutic options.

This article presents the recommendations of MDS experts of the Polish Adult Leukemia Group for the treatment of myelodysplastic syndromes, and for the management of conditions that are particularly common in patients with MDS i.e. infections, iron overload, and disease recurrence after hematopoietic cell transplantation. The aim of this study was to present a clear therapeutic algorithm to facilitate decision-making in everyday practice.

GUIDELINES/EXPERT CONSENSUS

Acta Haematologica Polonica 2022

Number 2, Volume 53, pages 75–93

DOI: 10.5603/AHP.a2022.0009

ISSN 0001–5814

e-ISSN 2300–7117

Treatment recommendations of Polish Adult Leukemia Group (PALG) for management of myelodysplastic syndromes (MDS) and other MDS-related conditions in Poland

Krzysztof Mądry1*iDBożena Katarzyna Budziszewska2Karol Lis1iDJoanna Drozd-Sokołowska1Bartłomiej Pogłódek3Rafał Machowicz1Edyta Subocz4Katarzyna Wiśniewska-Piąty5Tomasz Wróbel6Jan Maciej Zaucha7Ewa Zarzycka7Ewa Karakulska-Prystupiuk1Lidia Gil8Aleksandra Butrym9Agnieszka Tomaszewska1Grzegorz Władysław Basak1Anna Waszczuk-Gajda1Agnieszka Pluta10Paweł Szwedyk11Małgorzata Jarmuż-Szymczak12Jagoda Rytel1Jadwiga Dwilewicz-Trojaczek1
1Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
2Department of Hematology, Institute of Hematology and Transfusiology, Warszawa, Poland
3Department of Hematology, Jagiellonian University, Kraków, Poland
4Department of Hematology, Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration’s Hospital, Olsztyn, Poland
5Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland
6Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland
7Department of Hematology and Transplantology, Medical University of Gdansk, Gdańsk, Poland
8Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznań, Poland
9Department of Cancer Prevention and Therapy, Wroclaw Medical University, Wrocław, Poland
10Department of Hematology, Medical University of Łódź, Łódź, Poland
11Department of Hematology, Ludwik Rydygier Hospital, Kraków, Poland
12Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznań, Poland

*Address for correspondence: Krzysztof Mądry, Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw,
Banacha 1A, 02–097 Warszawa, Poland,
e-mail: kmadry@wum.edu.pl

Copyright © 2022
The Polish Society of Haematologists and Transfusiologists,
Insitute of Haematology and Transfusion Medicine.
All rights reserved.

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

Received: 18.10.2021 Accepted: 25.11.2021

Abstract
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 into acute myeloid leukemia. In recent years, significant progress in MDS biological research has allowed the addition of new drugs to the few existing therapeutic options.
This article presents the recommendations of MDS experts of the Polish Adult Leukemia Group for the treatment of myelodysplastic syndromes, and for the management of conditions that are particularly common in patients with MDS i.e. infections, iron overload, and disease recurrence after hematopoietic cell transplantation. The aim of this study was to present a clear therapeutic algorithm to facilitate decision-making in everyday practice.
Key words: myelodysplastic syndromes, treatment, recommendations
Acta Haematologica Polonica 2022; 53, 2: 75–93

Introduction

The choice of treatment for patients with myelodysplastic syndromes (MDS) is determined by the level of risk of transformation into acute myeloid leukemia (AML), as well as by the predicted overall survival time according to the prognostic scoring systems International Prognostic Scoring System (IPSS) and Revised International Prognostic Scoring System (IPSS-R):

the lower-risk group (MDS-LR) consists of patients with low and intermediate-1 risk according to IPSS, or very low, low, and intermediate risk with scores ≤3.5 according to IPSS-R;
the higher-risk group (MDS-LR) consists of patients with intermediate-2 or high risk according to IPSS, or intermediate with scores ≥4.0, high, or very high risk according to IPSS-R [1, 2].

The goal of treatment in lower-risk patients is to obtain hematological improvement, and the quality of life (QoL) improvement that comes with that. Taking into account the relatively favorable prognosis, and the toxicity of therapy, aggressive treatment is not usually used in this population (Figure 1).

148861.png
Figure 1. Therapeutic algorithm in patients with low-risk myelodysplastic syndromes (MDS); allo-HSCT — allogeneic hematopoietic stem cell transplantation; CsA — cyclosporine; ATG — anti-thymocyte globulin; ESA — erythropoiesis stimulating agent; G-CSF — granulocyte colony-
-stimulating factor; Hb — hemoglobin level; IPSS — International Prognostic Scoring System; IPSS-R — Revised International Prognostic Scoring System; MDS-LR — low-risk myelodysplastic syndrome; MDS-RS — MDS with ring sideroblasts; RBC-TD — red blood cell transfusion dependency

In higher-risk patients, depending on their general condition and the biological characteristics of the underlying disease, palliative or disease-modifying treatments (i.e. hypomethylating agents, chemotherapy) are used with the intention of prolonging survival and improving QoL or even as curative treatment [e.g. allogeneic hematopoietic stem cell transplantation (allo-HSCT)] (Figure 2).

148925.png
Figure 2. Therapeutic algorithm in patients with high-risk myelodysplastic syndromes (MDS); allo-HSCT — allogeneic hematopoietic stem cell transplantation; HMA — hypomethylating agent; IC — intensive chemotherapy; IPSS — International Prognostic Scoring System;
IPSS-R — Revised International Prognostic Scoring System; MDS-HR — high-risk myelodysplastic syndrome

Treatment response criteria

Treatment response is assessed according to the International Working Group (IWG) 2006 criteria, modified in 2018 for MDS-LR patients. Such responses include increases in blood cell count, reductions in the number of transfusions or transfusion independence, and reductions in bone marrow blasts percentages (Tables I and II) [3, 4].

Table I. 2006 International Working Group (IWG) myelodysplastic syndrome (MDS) response criteria (based on [3])

Category

Response criterion (must last at least 4 weeks)

Complete remission (CR)

Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines

Persistent dysplasia permissible

Hb: ≥11 g/dL, platelets: ≥100 G/L, neutrophils: ≥1.0 G/L, blasts: 0%

Partial remission (PR)

All CR criteria if abnormal before treatment, except bone marrow blasts decreased by ≥50% over pretreatment but still >5%

Marrow complete remission (mCR)

Bone marrow: ≤5% myeloblasts and decreased by ≥50% over pretreatment regardless of peripheral blood response

Stable disease (SD)

Failure to achieve CR and PR, but no evidence of progression for >8 weeks

Progressive disease (PD)

For patients with:

  • less than 5% blasts: 50% increase in blasts to 5% blasts
  • 5–10% blasts: 50% increase to 10% blasts
  • 10–20% blasts: 50% increase to 20% blasts
  • 20–30% blasts: 50% increase to 30% blasts

Any of the following:

  • at least 50% decrement from maximum remission/response in granulocytes or platelets
  • reduction in Hb by 2 g/dL
  • transfusion dependence

Relapse after CR or PR

At least one of the following:

Return to pretreatment bone marrow blast percentage

Decrement of ≥50% from maximum remission/response levels in granulocytes or platelets

Reduction in Hb concentration by ≥1.5 g/dL or transfusion dependence

Hematological improvement (HI)

Erythroid response (HI-E)
(pretreatment, <11 g/dL)

Response criteria (responses must last at least 8 weeks):

  • Hb increase by ≥1.5 g/dL
  • relevant reduction of units of RBC transfusions by ≥4 RBC transfusions/8 weeks

Platelet response (HI-PLT)
(pretreatment PLT <100 G/L)

  • absolute increase of ≥30 G/L for patients starting with <20 G/L platelets
  • increase from <20 G/L to ≥20 G/L and by at least 100%

Neutrophil response (HI-G)
(pretreatment <1.0 G/L)

  • at least 100% increase and an absolute increase >0.5 G/L

Table II. Revised International Working Group (IWG) 2018 hematological response criteria in patients with myelodysplastic syndrome (MDS) (based on [4])

Line

Pretreatment criteria

Response criteria

HI-E

NTD = (0 RBC in 16 weeks) [1]

Transfusion independent anemia:

0 RBC in 16 weeks

LTB:

3–7 RBC in 16 weeks in at least
2 TRSFN episodes

max 3 in 8 weeks

HTB:

≥8 RBC in 16 weeks

≥4 in 8 weeks

HI-E response:

at least 2 consecutive Hb measurements with increase of ≥1.5 g/dL for minimum of 8 weeks in observation period of 16–24 weeks

HI-E response:

TRSFN independence for minimum of 8 weeks in an observation period of 16–24 weeks

Major HI-E response:

TRSFN independent over a period of a minimum of 8 weeks in an observation period of 16–24 weeks

Minor HI-E:

reduction by at least 50% of RBC over a minimum of 16 weeks

Platelet response

20 G/L <PLT <100 G/L

0 <PLT < 20 G/L

Absolute increase of ≥30 G/L

Increase to >20 G/L and by at least 100%

Neutrophil response

NEU <1.0 G/L

At least 100% increase and absolute increase >0.5 G/L

Treatment of lower-risk patients

Blood product transfusions

Red blood cell (RBC) transfusions are given to prevent the serious complications of anemia, including heart failure and myocardial infarction. Chronic persistence of anemia, with hemoglobin (Hb) levels <9 g/dL in men and <8 g/dL in women, contributes to an increased risk of death and cardiovascular events [5, 6]. However, there is no data on the optimal time at which to start transfusions in MDS-LR patients, and the decision to transfuse RBC is based on clinical symptoms and Hb level.

Although the severity of anemia has a significant impact on the QoL of MDS patients, the Hb level at which RBC should be transfused has not been determined [7]. The only randomized study in MDS-LR patients comparing two thresholds for transfusion e.g. restrictive (8.0 g/dL, maintaining Hb level 8.5–10.0 g/dL) versus liberal (10.5 g/dL, maintaining Hb level 11.0–12.5 g/dL) favored the liberal versus the restrictive policy in relation to improvements in the five main QoL components [8].

The concept of RBC transfusion dependence (TD) is not clearly defined. The consensus is that patients who require two RBC concentrate units/month are transfusion-dependent. According to the 2018 IWG criteria, patients with red blood cell transfusion dependency (RBC-TD) are those who require a transfusion of ≥3 units/16 weeks [4]. RBC- -TD is associated with shorter survival and faster transformation into AML [9]. However, an European MDS Registry (EU-MDS Registry) analysis found that even transfusion <3 units/16 weeks was associated with an increased risk of MDS progression [10]. Accordingly, it may be that we should consider all patients receiving regular transfusions as TD. Recommendations for transfusion of RBC and platelet concentrates (PC) are set out in Tables III

Table III. Recommendations for red blood cell (RBC) transfusion in patients with low-risk myelodysplastic syndrome (MDS-LR) (based on [11–14])

Hb threshold for RBC transfusion should be individualized depending on:

  • comorbidities
  • symptoms at a given Hb level
  • observed clinical benefits after previous transfusions
  • patient preferences

No specific Hb level can be recommended as a threshold for RBC transfusion. But in asymptomatic patients with chronic anemia, Hb transfusion should be considered when Hb level is <8 g/dL

No single target Hb level can be recommended, but it should be taken into account that chronic anemia with Hb <8–9 g/dL significantly increases risk of cardiovascular disease and death

No limit on frequency or total number of units transfused lifelong into MDS patient

Frequency of transfusions should reflect duration of clinical benefit between transfusions

Routine RBC phenotypic selection is not recommended for all MDS patients treated with transfusions, but may be considered for patients with little improvement after RBC transfusions

Multiple recipients should be transfused with leukocyte-depleted preparations

[11–14] and IV

Table IV. Recommendations for platelets (PLT) transfusion in patients with low-risk myelodysplastic syndrome (MDS-LR) (based on [15–21]

Prophylactic PLT transfusion is not recommended in asymptomatic patients not receiving MDS modifying therapy

Preventive PLT transfusions (routinely transfuse only one PLT package (1 unit/10 kg bw):

  • in patients receiving intensive chemotherapy/hypomethylating drugs or undergoing allo-HSCT to maintain PLT levels ≥10 G/L, even without clinically significant bleeding (grade 0–1 and not requiring invasive procedures)
  • in patients in serious condition/seriously ill, even if there is no active bleeding or no invasive procedure planned
  • individual assessment of patients with chronic bleeding of WHO grade ≥2 according to symptoms severity and establishing strategies for prophylactic PLT transfusions, e.g. twice a week

In patients with bleeding, use of anti-fibrinolytic agents such as tranexamic acid should be considered [21]

[15–21]. Recommended platelets (PLT) level when performing invasive procedures are presented in Table V

Table V. Recommended platelets (PLT) level when performing invasive procedures [17–20]

Procedure

Recommended PLT level [G/L]

Placement of central catheters:

>20–30

  • tunneled
  • non-tunneled

Major surgery

>50

Lumbar puncture

≥40

Epidural catheter insertion/removal

≥80

Percutaneous liver biopsy

>50

Neurosurgery

Ophthalmic surgery for posterior segment of eye

>100

.

Erythropoiesis-stimulating agents

Erythropoiesis-stimulating agents (ESAs) are recommended as first-line treatment in MDS-LR patients with symptomatic anemia and Hb levels below 10 g/dL [2, 15]. Erythropoietin alpha has been registered in the European Union in this indication, and darbepoetin (approved only in the Unites States) is widely used in Poland and other European countries [22, 23]. The use of ESAs in patients with symptoms of anemia and higher Hb levels depends on individual clinician decision. Appropriate patient qualification determines the success of treatment. The validated and preferred predictive response model is the Nordic index.

The benefits of ESA treatment have been observed in patients with erythropoietin (EPO) levels below 500 U/L and a transfusion requirement of less than 2 RBC units/month (see Table VI)

Table VI. Predictive model of response to erythropoiesis-stimulating agents (ESA) treatments

Need for transfusions, point

EPO level [IU/L],
point

<2 RBC unit/month, 0

<500, 0

≥2 RBC unit/month, 1

≥500, 1

Anticipated response to ESA treatment:

score 0 = 74%, score 1 = 23%, score 2 = 7%

[24]. However, the greatest benefit is derived from starting ESA treatment before the patient becomes dependent on RBC transfusions. Initiating ESA treatment within 6 months of diagnosis improves response rates and delays the need for transfusion [25, 26].

Detailed information on the dosing and treatment regimen of ESA is provided in Figure 3.

149199.png
Figure 3. Algorithm of treatment with erythropoiesis stimulating proteins in patients with myelodysplastic syndromes (MDS); CBC — complete blood count; DAR — darbepoetin; EPO — erythropoietin; Fe — ferrum; G-CSF — granulocyte colony-stimulating factor; GFR — glomerular filtration rate; Hb — hemoglobin level; HI-E according to IWG 2018 — hematological improvement-erythroid response according to revised International Working Group (IWG) 2018 hematological response criteria; MDS-LR — low-risk myelodysplastic syndrome; MLD — multilineage dysplasia; N — normal level; PER — partial erythroid response; RS — ring sideroblasts; sEPO — serum erythropoietin; SLD — single lineage dysplasia; TIBC — total iron binding capacity; WBC — white blood cells

Treatment failure should only be considered after 24 weeks of ESA admini­stration, with or without granulocyte colony-stimulating factor (G-CSF).

The response rate to ESA treatment is 38–60%, median time to response to ESA is 2–3 months, and median duration of response is 18–24 months [22–24, 27]. For non-responders, increasing the ESA dose and adding G-CSF allows a response to be obtained in an additional c.20% of patients [28, 29]. Patients who achieve complete (Hb >11.5 g/dL) or partial (Hb elevation >1.5 g/dL and RBC independence but Hb <11.5 g/dL) RBC response should continue treatment at the lowest dose needed to maintain the response [24].

There is no clinical data describing the management of only a minor RBC response according to IWG 2018 (reduction in the number of RBC transfusions by half). However, it seems justified to continue treatment at the current doses or, if possible, with increased ESA doses or in combination with G-CSF.

Although the risk of thromboembolic complications in MDS patients treated with ESA is less than 2%, it seems appropriate to temporarily discontinue treatment if a rapid increase in hematocrit is observed, or if Hb level increases above 12 g/dL [22, 23, 30]. ESA can be re-started in a reduced dose, and responses should be carefully moni­tored [15].

The Polish Adult Leukemia Group (PALG) MDS working group’s indications for the treatment of ESA ± G-CSF are as follows patients in MDS LR group according to IPSS with:

symptomatic anemia (regardless of RBC-TD although it is optimal to start treatment before RBC transfusion demand is ≥2 units/month) and
EPO level <500 U/L

In non-responding patients or after loss of response to ESA some efficacy is shown by: lenalidomide, immunosuppressants, hypomethylating agents (HMA), luspatercept, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in selected cases.

Thrombopoietin receptor agonists

Thrombopoietin receptor agonists (TPO-RAs), romiplostim and eltrombopag are not approved for the treatment of thrombocytopenia in MDS-LR patients. Romiplostim at a dose of 500 to 1,500 µg weekly has increased platelet count in 36–65% of patients [31–33]. Eltrombopag at a dose of 150–300 mg/day has increased platelet count in 47% of MDS LR patients [34]. The use of both drugs allows for a significant reduction in the frequency of bleeding complications, and a reduction in the number of platelet transfusions. Some concerns have been raised by the impact of TPO-RA on the increased risk of transformation into AML. A transient increase in blasts percentage that resolves after drug discontinuation has been observed in 15% of patients, and a long-term follow-up did not confirm a higher transformation risk or increased mortality in patients receiving romiplostim [35]. The efficacy and safety of TPO-RA has not been confirmed in phase III studies, and therefore these drugs should be used with caution in clinical trials in patients with a blast percentage below 5%.

No phase III study has been conducted so far that would confirm the efficacy and safety of TPO-RA, and these drugs have not been approved for the treatment of patients with myelodysplastic syndromes in either the United States or Europe. Therefore they are not recommended by Polish experts in routine clinical practice.

It is worth noting however that TPO-RA may be a valuable therapeutic option in MDS-LR patients with severe thrombocytopenia in whom other therapeutic options (aza­citidine, allo-HSCT) are not considered. Neither of these drugs is reimbursed in Poland for this indication.

Granulocyte colony-stimulating factors

Neutropenia occurs in 15–20% of MDS-LR patients [36]. Although the use of G-CSFs increases the number of neutrophils in 60–75% of patients with neutropenia, chronic use of G-CSF is not recommended because it does not prolong survival in these patients. In addition, the possibility of transformation into AML, or progression to more advanced MDS, in patients treated with G-CSF has not been absolutely ruled out [37, 38]. G-CSFs are currently recommended in MDS LR patients with dominant neutropenia, but only with recurrent or severe infections [2, 39].

Lenalidomide

Lenalidomide at a dose of 10 mg for 21 days in 28-day cycles is recommended in MDS-LR patients with del5(q) who have lost a response or who are not candidates for ESA treatment [4, 5]. Erythroid response is achieved after 4–5 weeks in 61–76% of patients, RBC independence in 56–67% of patients, and 50–73% of patients achieve a cytogenetic response, including 29–45% of complete responses [40, 41]. Median overall survival in lenalidomide-treated patients is 3.5–4 years, and 5.7 years in patients who achieved transfusion independence.

The most common side effects of lenalidomide are neutropenia (75%) and thrombocytopenia (40%), with 70% of patients requiring drug discontinuation in the first month of treatment and subsequent dose reduction to 5 mg when restarted [42]. In recurrent neutropenia, 1–2 injections of G-CSF weekly should be considered. In cases of renal failure, the dose of lenalidomide should be reduced to a mi­nimum of 2.5 mg every other day. Due to the increased risk of thromboembolic events with lenalidomide, it is reasonable to use anticoagulation prophylaxis, especially when additional risk factors are present.

In Poland, lenalidomide is reimbursed only in patients with an isolated del5(q) and RBC dependence, although the National Comprehensive Cancer Network (NCCN) recommends the use of lenalidomide before the need for transfusion and in patients with an isolated chromosome 5 deletion. According to the European LeukemiaNet (ELN) guidelines, patients may have an additional cytogenetic aberration except chromosome 7 disorder or deletion 17. The TP53 gene mutation is found in c.20% of MDS patients with del5q and is a negative prognostic and predictive factor for response to lenalidomide, although the chance of RBC independence is comparable to that in patients without TP53 gene mutation.

In patients without del5(q) and transfusion dependence treated with lenalidomide, hematological improvement- -erythroid (HI-E) is achieved in 43% of patients, and RBC independence in 27% of patients, with a response duration of 8 months [43]. Treatment with lenalidomide in combination with ESA does not significantly alter treatment outcome: HI-E is achieved by 39% of patients, and RBC independence in 24% of patients with a response duration of 15 months [44]. Lenalidomide is not approved for the treatment of anemia in patients without del(5q), and its use is associated with the possibility of developing or worsening of neutropenia and thrombocytopenia.

Indications for lenalidomide treatment (all criteria must be met):

low-risk or intermediate-low-risk MDS according to IPSS;
isolated del5 (+ possibly an additional abnormality except chromosome 7 disorder or del 17);
symptomatic anemia and RBC independence (Hb 8–10 g/dL): dose of 5 mg or patients with RBC-TD: dose of 10 mg.
Luspatercept

Luspatercept was registered in 2020 in the European Union (EU) based on MEDALIST, a randomized phase III trial for the treatment of patients with (myelodysplastic syndrome with ring sideroblasts) MDS-RS subtype with RBC-TD who failed or were not eligible for ESA treatment. Luspatercept, a transforming growth factor beta (TGF-β) receptor inhibitor, unblocks the proper erythroblasts maturation and differentiation, acting synergistically with erythropoietin on the proliferation of immature red blood cells. In the MEDALIST [A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes] study, luspatercept administered subcutaneously at a dose of 1.0–1.75 mg/kg every 3 weeks resulted in RBC independence for at least 8 weeks in 47% of patients, and HI-E according to IWG 2006 criteria in 53% of patients. The median duration of transfusion independence was 30 weeks, and the median duration of HI-E was 83.6 weeks. The most common side effects in patients treated with luspatercept were weakness, diarrhea, nausea, and chills. Treatment was discontinued in 8% of patients due to grade 3 or more adverse events [45]. In patients with ring sideroblasts percentage <15%, luspatercept is slightly less effective, although the response rate is still 29–43% [46].

Immunosuppressive treatment

Immunosuppressive therapy (IST) can be used in MDS-LR patients with symptomatic cytopenia, with thrombocytopenia or neutropenia even in the first line [37], and in the case of anemia only after the failure of first and/or second line treatment. Although hypocellular bone marrow, the presence of HLA-DR 15, age less than 60 years, normal karyotype or trisomy 8, the presence of paroxysmal nocturnal hemoglobinuria (PNH) clone, and short RBC dependence duration are often considered to be predictors of a favorable response to IST, a study by Sloand et al. [47], and Stahl et al. [48] showed that none of these factors had predictive value for achieving ed blood cell transfusion dependency (RBC-TD), except for hypocellular bone marrow <20%.

Anti-thymocyte globulin (ATG) with or without cyclosporin is used for IST; horse ATG (h-ATG) is more effective, but it is only available in the United States [49]. A meta-analysis of trials with IST in MDS-LR patients showed 42% of responses and 33% of RBC independence. In the elderly, cyclosporine can be used as monotherapy, and the chances of achieving overall response (OR), HI-E, and transfusion independency (TI) are 47%, 50%, and 45%, respectively [48].

Other agents

HMA are not approved in the EU for use in MDS-LR patients, although 20–30% of ESA and/or lenalidomide failures achieve response [50, 51]. In patients with MDS LR, the use of 5-day treatment regimens allows for comparable efficacy as the 7-day courses, and with less toxicity [52]. Patients who have failed treatment with ESA and/or lenalidomide should be offered available clinical trials with new drugs whenever possible.

Iron chelating agents

Iron overload resulting from RBC transfusions (1 unit contains 200–250 mg of iron), and significant hyperferritinemia associated with e.g. ineffective iron metabolism, adversely affect overall survival in MDS patients [53–55]. Ferritin levels should be measured in MDS-LR patients every 12 weeks [15]. Chelation therapy should be started after an infusion of 20–25 units of RBC concentrate or when ferritin levels exceed 1,000 μg/L with the proviso that the patient’s non-MDS-related life expectancy exceeds 3 years, and always in HSCT candidates with iron overload regardless of IPSS risk score [56–58].

Deferoxamine is used at a dose of 30–40 mg/kg/day in infusions lasting many hours (e.g. 10–12 h) (subcutaneously or intravenously), at least 5 days a week, until the ferritin level drops below 1,000 µg/L. Deferasirox at a dose of 20–30 mg/kg can be used to obtain a ferritin concentration below 500 µg/L, but this drug is not reimbursed in Poland in adult patients.

In the prospective, randomized TELESTO [Myelodysplastic Syndromes (MDS) Event Free Survival With Iron Chelation Therapy] study, oral deferasirox (20–30 mg/kg) prolonged (2:1) the time to onset of hepatic and heart failure compared to a placebo [59].

Phlebotomy should be considered in patients after allogeneic hematopoietic cell transplantation who are still iron overloaded and no longer anemic.

The Polish experts recommend the use of iron chelators in patients with MDS with low or intermediate-1 risk score according to IPSS and:

with serum ferritin level >1,000 µg/L and/or
who received over 25 units of RBC concentrate;
with two patient-related factors (not related to MDS) that could shorten survival to less than 3 years.

Treatment of higher risk MDS patients

Chemotherapy (intensive and low-dose)

Anthracyclines and cytarne-based intensive chemotherapy (IC) in high-risk myelodysplastic syndrome (MDS-HR) patients has limited indications due to low efficacy and high toxicity. The complete remission (CR) rate is 36–60%, and is particularly low in patients with unfavorable prognostic karyotype. The duration of remission is short (10–12 months), and prolonged periods of aplasia are more common than in AML patients [60, 61].

Low doses of cytarne, e.g. 20 mg/m2/day for 14–21 days in 4-week cycles, make it possible to achieve CR/partial remission (PR) in 15–20% of patients, although their use is associated with a shorter overall survival compared to HMA, and therefore this treatment regimen is not recommended.

Intensive chemotherapy is recommended in patients:

with MDS-HR (>10% bone marrow blasts) without severe comorbidities, up to 65–69 years without unfavorable prognostic cytogenetics according to IPSS and IPSS-R and/or TP53 mutations/deletions
and who
are candidates for allo-HSCT (for remission).

The use of IC in patients who do not have a donor, or do not agree to allo-HSCT, is debatable.

Hypomethylating agents

Patients at higher risk according to IPSS who are not eligible for allo-HSCT are candidates for azacitidine treatment according to the Summary of Product Characteristics (SmPC). It should be noted however that some patients qualified for an allo-HSCT procedure may benefit from azacitidine as first-line treatment. According to the SmPC, the use of azacitidine in this group of patients is possible because at the time of commencing this drug the patient may not be eligible for allo-HSCT due to high MDS activity, and after several treatment cycles remission could be achieved, allowing for the transplantation. The dose of azacitidine is 75 mg/m2 administered subcutaneously for 7 days on/21 days off (28-day cycle). For organizational reasons, the drug can be administered within a 5-day schedule with a 2-day break (weekend) and then two consecutive days of drug administration (i.e. 5 + 2 + 2). The treatment results are similar to those of the 7-day regimen.

In patients treated with azacytidine, CR rate is 17%, PR rate 12%, and hematological improvement (HI) including possible CR and PR is 49%.

The median time to response is four treatment cycles, so it is important that the patient is able to receive at least three; 24–37% of patients receive up to three [62]. The response duration is 9–15 months, but much shorter (4 months) in patients with complex karyotype [63]. Patients who have achieved CR, PR, or hematological response (e.g. RBC, PLT transfusion independence) should receive the drug until disease progression or unacceptable toxicity. Discontinuation of azacitidine treatment leads to rapid progression.

The most common adverse reactions are grade 3–4 peripheral cytopenias: neutropenia (84%), thrombocytopenia (74%), anemia (54%), and grade 3–4 infections (30–60%). It is worth noting that, if possible, doses/intervals should not be modified due to hematological toxicity during the first three treatment cycles.

Decitne increases progression-free survival (PFS) but does not extend overall survival compared to best supportive care (BSC), so is not approved in the EU.

The prognosis of patients after the failure of azacitidine treatment is poor, with median survival of c.6 months.

Indications for treatment with azacitidine:

intermediate-2 and high-risk myelodysplastic syndromes according to the IPSS in patients not eligible for IC;
chronic myelomonocytic leukemia (CMML) with 10–29% bone marrow blasts without myeloproliferative disorder (WBC <13 G/L), in patients not eligible for IC;
acute myeloid leukemia with 20–30% blasts with multi-lineage dysplasia, according to World Health Organization (WHO) classification, in patients not eligible for IC;
AML with >30% bone marrow blasts according to WHO classification, in patients not eligible for IC;
bridging therapy in selected patients prior to allo-HSCT (in patients with unfavorable karyotype or aged >65);
higher-risk patients who have undergone allo-HSCT as relapse treatment, pre-treatment, or maintenance treatment.
Allogeneic hematopoietic stem cells transplantation in treatment of MDS

Despite the undoubted progress in the treatment of patients with MDS in recent years, allo-HSCT remains the only potentially curative method [64].

Patient-related and disease-related factors should be taken into account in the decision-making process of qualifying an MDS patient for allo-HSCT [56, 64–66]. Patient-related factors include: age, performance status according to Karnofsky performance scale (KPS), comorbidities (according to the augmented HCT-CI scale), psychosocial status, and patient preferences. The mean age of developing MDS is c.70, so it is particularly important to consider the qualification of some patients >65 years to allo-HSCT. Currently, it is believed that the chronological age (previously accepted upper age limit 65–75) is slightly less important than the biological age [assessment based, among others, on Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI), KPS, geriatric scales] [67].

‘Fit’ patients, i.e. those in whom an allo-HSCT procedure can be performed, are defined by the following parameters: KPS ≥70–80 and HCT-CI ≤3 (ELN 2020) [56].

High-risk patients with bone marrow blasts <10% and no medical contraindications for transplantation should be eligible for allo-HSCT as first-line therapy provided they have an available donor. Best long-term results were achieved when pre-transplant blasts <5%. Conversely, when bone marrow blasts are 10% or greater, the patient should receive cytoreduction therapy prior to transplantation. The clinical outcomes of the use of azacitidine or intensive chemotherapy as cytoreduction are comparable [68].

Hematopoietic stem cells transplantation is a potential option for ‘fit’ patients from the higher risk group according to IPSS or IPSS-R, and in lower risk (IPSS) or moderate/lower risk (IPSS-R) patients with:

unfavorable cytogenetic disorders;
a 50% increase in blasts or bone marrow blasts >15%;
life-threatening cytopenias defined as:
absolute neutrophil count (ANC) <0.3 G/L,
PLT <30 G/L,
RBC-TD of at least 2 units/month for 6 months.

The long-term outcome of allo-HSCT in MDS patients and the peri-transplant risk have been assessed in several prognostic indices, among which the predictive model by Della Porta et al. (based on age, HCT-CI, karyotype, IPSS-R and response to induction chemotherapy) and the so-called European Group for Blood and Marrow Transplantation (EBMT) transplant-specific risk score for MDS, are the most widely used [65, 69].

When qualifying an MDS patient for a transplant procedure, the optimal preparation method should be considered, i.e. conditioning. The choice of myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) depends primarily on the patient’s age and the presence of comorbidities. In the randomized, multicenter EBMT clinical trial, the results of RIC versus MAC use were comparable, with 2-year survival rates of 76.3% and 63.2%, respectively [70]. In this study, patients >60 years accounted for only 4%. The decision to select specific conditioning regimens is generally based on site preferences and experience [70–73]. In recent years, a fludarne/treosulfan regimen with relatively low toxicity has been successfully used. In Wedge et al.’s study [74], 3-year overall survival rate after fludarne/treosulfan-based conditioning was 71%. In the group receiving the standard MAC regimen [total body irradiation (TBI)/cyclophosphamide or busulfan/cyclophosphamide] it was 52.8%, and in the group receiving RIC it was 62% (p = 0.075) [74].

Today, for the vast majority of patients, it is possible to match a donor of hematopoietic cells: the first choice is a related donor fully matched with human leukocyte antigen (HLA) antigens, the second choice is a fully matched or other acceptable unrelated donor, and the next best is a haploidentical donor.

Azacitidine in patients after allo-HSCT

The most common cause of allo-HSCT failure in patients with MDS and AML is disease relapse (30–70% of patients) [75]. Survival rate in patients with relapse after allo-HSCT is low, e.g. 2-year survival rate below 10–20%.

Recent reports indicate that in a selected population of MDS patients with relapse after transplantation, the treatment strategy may be even more important for overall survival than pre-transplant cytoreduction [76].

Due to the genetic heterogeneity of AML/MDS and the risk of clonal evolution after transplantation, it is helpful to simultaneously use several assessment methods for remission monitoring. Standard recommendations regarding optimal minimal residual disease (MRD) measurement intervals after transplantation have not yet been established.

The following are relapse definitions [77–81]:

cytometric, according to ELN AML 2017, is defined at MRD cut-off level >0.1%;
molecular: an increase in MRD level of ≥1 log10 between 2 positive samples in a previously negative patient;
hematological relapse of MDS after alloHSCT: bone marrow blasts 5–20% and/or reappearance of myelodysplastic features associated with cytopenia or auto­logous regeneration in chimerism testing;
hematological relapse of MDS with progression to AML: bone marrow blasts exceeding 20%;
hematological relapse of AML after allo-HSCT: bone marrow blasts equal to or greater than 5%, peripheral blood blasts or extramedullary leukemia.

Complete chimerism (CC) and mixed chimerism (MC) means >95% and ≤95, respectively, of donor cells in the selected fraction of tested cells [82]. Currently, the most commonly used treatments of MDS/AML relapse after allo-HSCT are hypomethylating agents, especially azacitidine, often in combination with donor lymphocyte infusions (DLI). The principles of maintenance treatment, pre-treatment and relapse treatment are summarized in Table VII

Table VII. Principles of azacitidine (AZA) treatment after allogeneic hematopoietic stem cell transplantation (allo-HSCT) (based on [83–92])

Consolidation treatment

General guidelines

Heterogeneous group due to limitations of MRD diagnostics

Indications

Patients in complete remission and with full chimerism with high risk of recurrence:

  • high-risk cytogenetic features — complex karyotypes and/or TP53 mutations
  • initially advanced disease (except for CR1 before transplantation)
  • history of treatment-resistant disease
  • no possibility of using targeted therapy (e.g. FLT3 inhibitors, IDH)
  • application of RIC conditioning

Dose

32 mg/m2/d for 5 days, 28-day regimen

Initiation treatment time

30–100 days after allo-HSCT

Treatment duration

Not established, 4 to 12 cycles were used

Summary

Treatment not routinely recommended

Preemptive treatment

General guidelines

Systematic MRD monitoring recommended

Indications

Patients with MRD, molecular relapse, and/or progressive mixed chimerism

Dose

75 mg/m2/d for 7 days, 28-day regimen

Initiation treatment time

Early disease detection and immediate treatment initiation from day 30 after allo-HSCT

Treatment duration

Not established, from 6 to 12 or even 24 cycles

DLI administration to be considered every other cycle

Summary

Standard management

Treatment of hematological relapse

General guidelines

Combination with cell therapy (DLI) or targeted therapy indicated

Indications

Patients with hematological relapse

Dose

75 mg/m2/d for 7 days, 28-day regimen

Initiation treatment time

Early detection of disease and immediate initiation of treatment is essential

Treatment duration

Administered chronically, discontinuation of treatment is associated with disease relapse

Summary

Transient treatment effect

This may be a bridge strategy to II allo-HSCT

[83–92].

Hypoplastic myelodysplastic syndromes

Decreased bone marrow cellularity is found in 10–20% of MDS patients, and this is the basis for the diagnosis of the hypoplastic form of this disease [hypoplastic MDS (h-MDS)]. To date, no precise definition of h-MDS has been developed, but the usual borderline value is bone marrow cellularity below 20–30%. According to the WHO classification, h-MDS is not a separate subtype of myelodysplastic syndrome. Patients with h-MDS are younger, with less severe anemia, but with deeper neutropenia and thrombocytopenia compared to patients with normo-/hypercellular bone marrow. The distribution of particular prognostic groups according to IPSS does not differ depending on the marrow cellularity. The clinical course of this disease is characterized by greater effectiveness of immunosuppressive treatment and a better prognosis compared to typical MDS.

Primarily, aplastic anemia (AA) should be considered in the differential diagnosis [93, 94].

Myelodysplastic syndromes with bone marrow fibrosis

According to the WHO 2016 classification, myelodysplastic syndrome with bone marrow fibrosis (MDS-F) is not a separate subtype of MDS, although a provisional subtype has been distinguished: myelodysplastic syndromes with excess of blasts and fibrosis, known as MDS-EB-F or MDS-F [95]. Most patients with MDS-F have an increased percentage of bone marrow blasts. Unlike primary myelofibrosis, patients with MDS-F usually do not have splenomegaly or leukoerythroblastosis. MDS-F includes patients with grade 2 or more fibrosis (10–15% of MDS).

The presence of advanced fibrosis worsens the prognosis, increases mortality [96] and shortens the time to transformation into AML [97]. Due to the difficulties in obtaining a reliable bone marrow for cytological examination, trephine biopsy is a valuable supplementary test in assessing the percentage of blasts. It has been shown that in MDS-F, grade 3 fibrosis correlates with an increased percentage of blasts, increased lactate dehydrogenase (LDH) activity, lower number of platelets, greater RBC dependence, multilinear dysplasia, complex karyotype, and the presence of molecular disorders (in TP53, SETBP1 genes). JAK2 gene mutation has not been found to be more frequent, which may help differential diagnosis.

Advanced fibrosis (BMF 3) has been shown not to worsen the response to hypomethylating agents and lenalidomide, but it has not yet been established whether their use in low-risk groups reduces fibrosis [96].

Fibrosis worsens transplantation outcomes by delaying cell reconstitution and increasing the risk of graft failure. The probability of 3-year overall survival in MDS patients with stage 3 fibrosis is only 21%, compared to 40–49% in patients with grade 0–2 fibrosis. Fibrosis does not influence the risk and course of graft-versus-host disease (GvHD) [98].

Therapy-related myelodysplastic syndromes

Therapy-related myelodysplastic syndromes (t-MDS) are a group of diseases that are a late complication after chemo- and/or radiotherapy used in the treatment of neoplastic and non-neoplastic diseases [95]. t-MDS accounts for c.10–20% of all myelodysplastic syndromes [99]. Among neoplastic diseases, 70% of newly diagnosed t-MDS are preceded by therapy of solid tumors, and 30% by treatment of hematological malignancies [95]. The incidence of t-MDS after treatment with conventional chemotherapy is 0.8–6.3% over 20 years, and after high-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) is 1.1–24.3% over 5 years [100]. The prognosis in patients with t-MDS is worse than in patients with pMDS, with overall survival of 5–34 months [101].

Therapy of t-MDS includes hypomethylating agents, conventional chemotherapy, adjuvant therapy, and allo-HSCT, which remains the only potentially curative form of therapy [102].

Prevention and treatment of infections in myelodysplastic syndromes

The risk of infections in MDS patients is the result of immune disorders occurring in the course of disease, general condition, comorbidities and treatment complications [103–106]. Infectious complications account for 30–38% of all death causes [107].

The most common infectious complications in the course of MDS are febrile neutropenia (36–47%), pneumonia (21–50%) and sepsis (14%) [108, 109]. The most common is bacterial etiology, accounting for 80% of infections (caused by both Gram-positive and Gram-negative bacteria), but they are usually diagnosed clinically, and microbiological confirmation is achieved only in c.30% of patients.

In recent years, attention has turned to the increased incidence of invasive mycoses, including mucormycosis, in this group of patients. Viral infections [except for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] are rare in conventionally treated patients, although influenza can have a severe course in patients with myelodysplastic syndromes.

The risk of infection depends on the severity of the underlying disease; in MDS-LR patients treated with azacitidine, the risk of grade 3–4 infections is c.9.5–26% and is significantly lower than in MDS-HR patients (43–71%) [110, 111]. Infections most often occur within the first three treatment cycles of azacitidine (66% of all infections).

Based on a retrospective analysis of 298 patients performed by the PALG MDS Working Group, a model of infection risk in patients treated with azacitidine has been developed with the following risk factors identified: RBC-TD, neutropenia <0.8 G/L, thrombocytopenia <50 G/L, hypoalbuminemia <3.5 g/dL, and Eastern Co-operative Oncology Group Performance Status (ECOG PS) ≥2.

Patients with three, four, or all five of the abovementioned factors had a significantly higher risk of infection (73%) compared to patients with 0–2 risk factors (25%) [108]. In this study, mortality in patients with sepsis, pneumonia, and febrile neutropenia was 45%, 26%, and 15%, respectively. Based on preliminary data, SARS-CoV-2 infection in MDS patients is associated with a very high risk of death, reaching 42–47% [112].

Although there is no clear indication for pharmacological prophylaxis in all patients treated with azacitidine, it should be considered in specific risk groups [113]. The efficacy of fluoroquinolone-based antibacterial prophylaxis has been confirmed in patients treated with decitne [114]. It remains unclear which antifungal agents should be used in this group of patients, and in particular whether to use azoles with proven efficacy against molds [115]. Recommendations regarding the prevention of infection in MDS patients for whom treatment is planned are set out in Table VIII.

Table VIII. Recommendations for infection prophylaxis in myelodysplastic syndrome (MDS) patients with planned treatment

Infection type

Diagnostic tests

Prophylaxis

Hepatitis B, C


HIV

HBsAg, anti-HCV

Anti-HBc, (HBV DNA), anti-HBsAg, (HCV RNA) — optionally

HIV combi

Tuberculosis

IGRA, tuberculin test — optional

Colonization with MRB (ESBL, VRE, MBL)

Outpatient — no

Hospitalized — yes (rectal swab with culture)

No

Invasive mycoses

Galactomannan antigen

Only in patients treated with IC-posaconazole

In patients undergoing allo-HSCT: same procedure as
in other transplant patients

Bacteria

Primary: only at high risk Secondary: quinolones

G-CSF: to be considered only when infection with neutropenia

Immunization

HSV, CMV, EBV, parvovirus B19

Routinely not

Streptococus pneumoniae, Flu, SARS CoV-2 — yes

Acyclovir only in case of recurrent HSV reactivation

New agents in myelodysplastic syndrome treatment

In recent years, many clinical trials with the use of new molecules have been conducted in patients with myelodysplastic syndromes. After many years without new effective drugs, the latest results of phase II and III studies are generating optimism regarding the addition of new agents to what is still a relatively modest armamentarium (Table IX)

Table IX. Clinical trials with selected new agents for myelodysplastic syndrome (MDS) treatment

Agent

MoA

Studied cohort

Phase

Results

Reference

Imetelstat

Telomerase inhibitor

LR-MDS

RBC-TD, r/r ESA

or EPO >500 U/L

II

III

RBC-TI 42%

(HI-E 68%)

Ongoing (2023)

[116]

Roxadustat

Inhibition of HIFα degradation

LR-MDS

RBC-TD LTB, non-del 5q, EPO <400 U/L

III (OL)

III

RBC-TI 38%

(HI-E 63%)

Ongoing (2021)

[117]

Venetoclax

BCL-2 inhibitor

HR MDS: venetoclax + AZA

(I line)

HMA r/r

Venetoclax + AZA (II line)

Ib

III

OR 79% (CR 39.7%)

OR 39% (CR 7%)

[118, 119]

Pevonedistat

Neddylation inhibitor

HR-MDS

HMA r/r

Pevonedistat + AZA

Pevonedistat + AZA (I line)

II

III

OR 42% (CR, mCR, HI)

OR 79% (CR, PR, HI)

[120, 121]

Magrolimab

CD47 inhibitor

MDS-HR (I line)

Magrolimab + AZA

Ib

III

OR 100% (CR 53%)

Ongoing

[122]

Eprenetapopt

APR-246

Restoring p53 function

HR MDS with TP53 mutation (+ AZA)

Ib/II

III

OR 73% (CR 50%, CCR 58%)

Ongoing

[123]

Rigosertib

RAS pathway affector inhibitor:
PI3K and PLK

HR MDS
Rigosertib + AZA
(I line)

HMA r/r
Rigosertib
± AZA
(I line)


II



III


OR 92% (CR 34%)



OR 54% (CR 4%)

Ongoing

[124]

.

Authors’ contributions

Conception and design: KM, JDT. Manuscript writing, final approval of the manuscript: all authors.

Conflict of interest

None.

Financial support

None.

Ethics

The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal experiments; uniform requirements for manuscripts submitted to Biomedical journals.

References

  1. Pfeilstöcker M, Tuechler H, Sanz G, et al. Time-dependent changes in mortality and transformation risk in MDS. Blood. 2016; 128(7): 902–910, doi: 10.1182/blood-2016-02-700054, indexed in Pubmed: 27335276.
  2. Fenaux P, Haase D, Santini V, et al. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32(2): 142–156, doi: 10.1016/j.annonc.2020.11.002, indexed in Pubmed: 33221366.
  3. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006; 108(2): 419–425, doi: 10.1182/blood-2005-10-4149, indexed in Pubmed: 16609072.
  4. Platzbecker U, Fenaux P, Adès L, et al. Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials. Blood. 2019; 133(10): 1020–1030, doi: 10.1182/blood-2018-06-857102, indexed in Pubmed: 30404811.
  5. Malcovati L, Della Porta MG, Strupp C, et al. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS). Haematologica. 2011; 96(10): 1433–1440, doi: 10.3324/haematol.2011.044602, indexed in Pubmed: 21659359.
  6. Oliva EN, Schey C, Hutchings AS. A review of anemia as a cardiovascular risk factor in patients with myelodysplastic syndromes. Am J Blood Res. 2011; 1(2): 160–166, indexed in Pubmed: 22432077.
  7. Stauder R, Yu Ge, Koinig KA, et al. Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study. Leukemia. 2018; 32(6): 1380–1392, doi: 10.1038/s41375-018-0089-x, indexed in Pubmed: 29572506.
  8. Stanworth SJ, Killick S, McQuilten ZK, et al. REDDS Investigators. Red cell transfusion in outpatients with myelodysplastic syndromes: a feasibility and exploratory randomised trial. Br J Haematol. 2020; 189(2): 279–290, doi: 10.1111/bjh.16347, indexed in Pubmed: 31960409.
  9. Sekeres MA, Maciejewski JP, List AF, et al. Perceptions of disease state, treatment outcomes, and prognosis among patients with myelodysplastic syndromes: results from an internet-based survey. Oncologist. 2011; 16(6): 904–911, doi: 10.1634/theoncologist.2010-0199, indexed in Pubmed: 21478277.
  10. de Swart L, Crouch S, Hoeks M, et al. Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes. Haematologica. 2020; 105(3): 632–639, doi: https://doi.org/10.3324/haematol.2018.212217.
  11. Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2012; 157(1): 49–58, doi: 10.7326/0003-4819-157-1-201206190-00429, indexed in Pubmed: 22751760.
  12. Gu Y, Estcourt LJ, Doree C, et al. Comparison of a restrictive versus liberal red cell transfusion policy for patients with myelodysplasia, aplastic anaemia, and other congenital bone marrow failure disorders. Cochrane Database Syst Rev. 2015; 3(CD011577), doi: 10.1002/14651858.CD011577, indexed in Pubmed: 25983657.
  13. Mo A, McQuilten ZK, Wood EM, et al. Red cell transfusion thresholds in myelodysplastic syndromes: a clinician survey to inform future clinical trials. Intern Med J. 2017; 47(6): 695–698, doi: 10.1111/imj.13434, indexed in Pubmed: 28580745.
  14. EU MDS Registry. https://nmds.org (October 18, 2021).
  15. Killick SB, Ingram W, Culligan D, et al. British Society for Haematology guidelines for the management of adult myelodysplastic syndromes. Br J Haematol. 2021; 194(2): 267–281, doi: 10.1111/bjh.17612, indexed in Pubmed: 34180045.
  16. Killick SB, Carter C, Culligan D. Guidelines for the diagnosis and management of adult myelodysplastic syndromes. Br J Haematol. 2014; 164(4): 503–525, doi: 10.1111/bjh.12694, indexed in Pubmed: 24372298.
  17. Estcourt LJ, Birchall J, Allard S, et al. Guidelines for the use of platelet transfusions. Br J Haematol. 2017; 176(3): 365–394, doi: 10.1111/bjh.14423, indexed in Pubmed: 28009056.
  18. Schiffer CA, Bohlke K, Delaney M, et al. Platelet transfusion for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2018; 36(3): 283–299, doi: 10.1200/jco.2017.76.1734.
  19. Liumbruno G, Bennardello F, Lattanzio A, et al. Recommendations for the transfusion of plasma and platelets. Blood Transfus. 2009; 7(2): 132–150, doi: 10.2450/2009.0005-09, indexed in Pubmed: 19503635.
  20. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet transfusion: a cinical practice guideline from the AABB. Ann Intern Med. 2015; 162(3): 205–213, doi: 10.7326/m14-1589.
  21. Desborough M, Hadjinicolaou AV, Chaimani A, et al. Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review. Cochrane Database Syst Rev. 2016; 10: CD012055, doi: 10.1002/14651858.CD012055.pub2, indexed in Pubmed: 27797129.
  22. Fenaux P, Santini V, Spiriti MA, et al. A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia. 2018; 32(12): 2648–2658, doi: 10.1038/s41375-018-0118-9, indexed in Pubmed: 29895954.
  23. Platzbecker U, Symeonidis A, Oliva EN, et al. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017; 31(9): 1944–1950, doi: 10.1038/leu.2017.192, indexed in Pubmed: 28626220.
  24. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. Scandinavian MDS Group. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003; 120(6): 1037–1046, doi: 10.1046/j.1365-2141.2003.04153.x, indexed in Pubmed: 12648074.
  25. Garelius HKG, Johnston WT, Smith AG, et al. Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome. J Intern Med. 2017; 281(3): 284–299, doi: 10.1111/joim.12579, indexed in Pubmed: 27926979.
  26. Park S, Kelaidi C, Sapena R, et al. Early introduction of ESA in low risk MDS patients may delay the need for RBC transfusion: a retrospective analysis on 112 patients. Leuk Res. 2010; 34(11): 1430–1436, doi: 10.1016/j.leukres.2010.05.030, indexed in Pubmed: 20580086.
  27. Greenberg PL, Sun Z, Miller KB, et al. Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996). Blood. 2009; 114(12): 2393–2400, doi: 10.1182/blood-2009-03-211797, indexed in Pubmed: 19564636.
  28. Park S, Greenberg P, Yucel A, et al. Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review. Br J Haematol. 2019; 184(2): 134–160, doi: 10.1111/bjh.15707, indexed in Pubmed: 30549002.
  29. Kelaidi C, Park S, Sapena R, et al. Long-term outcome of anemic lower-risk myelodysplastic syndromes without 5q deletion refractory to or relapsing after erythropoiesis-stimulating agents. Leukemia. 2013; 27(6): 1283–1290, doi: 10.1038/leu.2013.16.
  30. Park S, Fenaux P, Greenberg P, et al. Efficacy and safety of darbepoetin alpha in patients with myelodysplastic syndromes: a systematic review and meta-analysis. Br J Haematol. 2016; 174(5): 730–747, doi: 10.1111/bjh.14116, indexed in Pubmed: 27214305.
  31. Giagounidis A, Mufti GJ, Fenaux P, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014; 120(12): 1838–1846, doi: 10.1002/cncr.28663, indexed in Pubmed: 24706489.
  32. Kantarjian H, Fenaux P, Sekeres MA, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010; 28(3): 437–444, doi: 10.1200/JCO.2009.24.7999, indexed in Pubmed: 20008626.
  33. Sekeres MA, Kantarjian H, Fenaux P, et al. Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk myelodysplastic syndromes. Cancer. 2011; 117(5): 992–1000, doi: 10.1002/cncr.25545, indexed in Pubmed: 20945323.
  34. Oliva EN, Alati C, Santini V, et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017; 4(3): e127–e136, doi: 10.1016/s2352-3026(17)30012-1.
  35. Kantarjian HM, Fenaux P, Sekeres M, et al. Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial. Lancet Haematol. 2018; 5(3): e117–e126, doi: 10.1016/s2352-3026(18)30016-4.
  36. Girmenia C, Candoni A, Delia M, et al. Infection control in patients with myelodysplastic syndromes who are candidates for active treatment: Expert panel consensus-based recommendations. Blood Rev. 2019; 34: 16–25, doi: 10.1016/j.blre.2018.10.002, indexed in Pubmed: 30448050.
  37. Fenaux P, Platzbecker U, Ades L. How we manage adults with myelodysplastic syndrome. Br J Haematol. 2020; 189(6): 1016–1027, doi: 10.1111/bjh.16206, indexed in Pubmed: 31568568.
  38. Hutzschenreuter F, Monsef I, Kreuzer KA, et al. Granulocyte and granulocyte-macrophage colony stimulating factors for newly diagnosed patients with myelodysplastic syndromes. Cochrane Database Syst Rev. 2016; 2: CD009310, doi: 10.1002/14651858.CD009310.pub2, indexed in Pubmed: 26880256.
  39. Greenberg PL, Stone R, Al-Kali A, et al. Myelodysplastic syndromes, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016; 15(1): 60–87, doi: 10.6004/jnccn.2017.0007.
  40. Fenaux P, Giagounidis A, Selleslag D, et al. MDS-004 Lenalidomide del5q Study Group. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011; 118(14): 3765–3776, doi: 10.1182/blood-2011-01-330126, indexed in Pubmed: 21753188.
  41. Giagounidis A, Fenaux P, Mufti GJ, et al. Practical recommendations on the use of lenalidomide in the management of myelodysplastic syndromes. Ann Hematol. 2008; 87(5): 345–352, doi: 10.1007/s00277-008-0449-0, indexed in Pubmed: 18265982.
  42. Volpe VO, Komrokji RS. Treatment options for lower-risk myelodysplastic syndromes. Where are we now? Ther Adv Hematol. 2021; 12: 2040620720986641, doi: 10.1177/2040620720986641, indexed in Pubmed: 33505645.
  43. Santini V, Almeida A, Giagounidis A, et al. Randomized phase III study of lenalidomide versus placebo in RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes and ineligible for or refractory to erythropoiesis-stimulating agents. J Clin Oncol. 2016; 34(25): 2988–2996, doi: 10.1200/jco.2015.66.0118.
  44. Toma A, Kosmider O, Chevret S, et al. Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. Leukemia. 2015; 30(4): 897–905, doi: 10.1038/leu.2015.296.
  45. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020; 382(2): 140–151, doi: 10.1056/NEJMoa1908892, indexed in Pubmed: 31914241.
  46. Radsak M, Platzbecker U, Schmidt CS, et al. Infectious complications in patients with myelodysplastic syndromes: a review of the literature with emphasis on patients treated with 5-azacitidine. Eur J Haematol. 2017; 99(2): 112–118, doi: 10.1111/ejh.12883, indexed in Pubmed: 28321924.
  47. Sloand EM, Olnes MJ, Shenoy A, et al. Alemtuzumab treatment of intermediate-1 myelodysplasia patients is associated with sustained improvement in blood counts and cytogenetic remissions. J Clin Oncol. 2010; 28(35): 5166–5173, doi: 10.1200/JCO.2010.29.7010, indexed in Pubmed: 21041705.
  48. Stahl M, Bewersdorf JP, Giri S, et al. Use of immunosuppressive therapy for management of myelodysplastic syndromes: a systematic review and meta-analysis. Haematologica. 2020; 105(1): 102–111, doi: 10.3324/haematol.2019.219345, indexed in Pubmed: 31004015.
  49. Stahl M, DeVeaux M, de Witte T, et al. The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort. Blood Adv. 2018; 2(14): 1765–1772, doi: 10.1182/bloodadvances.2018019414, indexed in Pubmed: 30037803.
  50. Tobiasson M, Dybedahl I, Holm MS, et al. Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial. Blood Cancer J. 2014; 4: e189, doi: 10.1038/bcj.2014.8, indexed in Pubmed: 24608733.
  51. Thépot S, Ben Abdelali R, Chevret S, et al. Groupe Francophone des Myélodysplasies (GFM). A randomized phase II trial of azacitidine +/- epoetin-β in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents. Haematologica. 2016; 101(8): 918–925, doi: 10.3324/haematol.2015.140988, indexed in Pubmed: 27229713.
  52. Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol. 2009; 27(11): 1850–1856, doi: 10.1200/JCO.2008.17.1058, indexed in Pubmed: 19255328.
  53. Leitch HA, Parmar A, Wells RA, et al. Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient-related factors and measuring from time of first red blood cell transfusion dependence: an MDS-CAN analysis. Br J Haematol. 2017; 179(1): 83–97, doi: 10.1111/bjh.14825, indexed in Pubmed: 28677895.
  54. Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005; 23(30): 7594–7603, doi: 10.1200/JCO.2005.01.7038, indexed in Pubmed: 16186598.
  55. Waszczuk-Gajda A, Mądry K, Machowicz R, et al. Red blood cell transfusion dependency and hyperferritinemia are associated with impaired survival in patients diagnosed with myelodysplastic syndromes: results from the first Polish MDS-PALG Registry. Adv Clin Exp Med. 2016; 25(4): 633–641, doi: 10.17219/acem/62397, indexed in Pubmed: 27629836.
  56. de Witte T, Bowen D, Robin M, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017; 129(13): 1753–1762, doi: 10.1182/blood-2016-06-724500, indexed in Pubmed: 28096091.
  57. Majhail NS, Lazarus HM, Burns LJ. A prospective study of iron overload management in allogeneic hematopoietic cell transplantation survivors. Biol Blood Marrow Transplant. 2010; 16(6): 832–837, doi: 10.1016/j.bbmt.2010.01.004, indexed in Pubmed: 20079863.
  58. Brissot E, Savani BN, Mohty M. Management of high ferritin in long-term survivors after hematopoietic stem cell transplantation. Semin Hematol. 2012; 49(1): 35–42, doi: 10.1053/j.seminhematol.2011.10.003, indexed in Pubmed: 22221783.
  59. Angelucci E, Greenberg P, Izquierdo M, et al. Iron chelation in transfusion-dependent patients with low- to intermediate-1-risk myelodysplastic syndromes. Ann Intern Med. 2020; 173(7): 595–596, doi: 10.7326/L20-1056, indexed in Pubmed: 33017548.
  60. Fenaux P, Mufti G, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009; 10(3): 223–232, doi: 10.1016/s1470-2045(09)70003-8.
  61. Knipp S, Hildebrand B, Kündgen A, et al. Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes. Cancer. 2007; 110(2): 345–352, doi: 10.1002/cncr.22779, indexed in Pubmed: 17559141.
  62. Mozessohn L, Cheung MC, Fallahpour S, et al. Azacitidine in the ‘real-world’: an evaluation of 1101 higher-risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario, Canada. Br J Haematol. 2018; 181(6): 803–815, doi: 10.1111/bjh.15273, indexed in Pubmed: 29767427.
  63. Itzykson R, Thépot S, Quesnel B, et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood. 2011; 117(2): 403–411, doi: 10.1182/blood-2010-06-289280.
  64. Carreras E, Dufour C, Mohty M M, Kröger NT. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. Springer International Publishing, [MIASTO??] 2018.
  65. Porta MD, Alessandrino E, Bacigalupo A, et al. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R. Blood. 2014; 123(15): 2333–2342, doi: 10.1182/blood-2013-12-542720.
  66. Vaughn JE, Storer BE, Armand P, et al. Design and validation of an augmented Hematopoietic Cell Transplantation-Comorbidity Index comprising pretransplant ferritin, albumin, and platelet count for prediction of outcomes after allogeneic transplantation. Biol Blood Marrow Transplant. 2015; 21(8): 1418–1424, doi: 10.1016/j.bbmt.2015.04.002, indexed in Pubmed: 25862589.
  67. Lim Z, Brand R, Martino R, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol. 2010; 28(3): 405–411, doi: 10.1200/JCO.2009.21.8073, indexed in Pubmed: 20008642.
  68. Potter VT, Iacobelli S, van Biezen A, et al. Comparison of intensive chemotherapy and hypomethylating agents before allogeneic stem cell transplantation for advanced myelodysplastic syndromes: a study of the Myelodysplastic Syndrome Subcommittee of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2016; 22(9): 1615–1620, doi: 10.1016/j.bbmt.2016.05.026, indexed in Pubmed: 27264633.
  69. Gagelmann N, Eikema DJ, Stelljes M, et al. Optimized EBMT transplant-specific risk score in myelodysplastic syndromes after allogeneic stem-cell transplantation. Haematologica. 2019; 104(5): 929–936, doi: 10.3324/haematol.2018.200808, indexed in Pubmed: 30655377.
  70. Kröger N, Iacobelli S, Franke GN, et al. Dose-reduced versus standard conditioning followed by allogeneic stem-cell transplantation for patients with myelodysplastic syndrome: a prospective randomized phase III study of the EBMT (RICMAC trial). J Clin Oncol. 2017; 35(19): 2157–2164, doi: 10.1200/JCO.2016.70.7349, indexed in Pubmed: 28463633.
  71. Koreth J, Pidala J, Perez WS, et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J Clin Oncol. 2013; 31(21): 2662–2670, doi: 10.1200/JCO.2012.46.8652, indexed in Pubmed: 23797000.
  72. Festuccia M, Deeg HJ, Gooley TA, et al. Minimal identifiable disease and the role of conditioning intensity in hematopoietic cell transplantation for myelodysplastic syndrome and acute myelogenous leukemia evolving from myelodysplastic syndrome. Biol Blood Marrow Transplant. 2016; 22(7): 1227–1233, doi: 10.1016/j.bbmt.2016.03.029, indexed in Pubmed: 27064057.
  73. Deeg HJ, Stevens EA, Salit RB, et al. Transplant conditioning with treosulfan/fludarabine with or without total body irradiation: a randomized phase II trial in patients with myelodysplastic syndrome and acute myeloid leukemia. Biol Blood Marrow Transplant. 2018; 24(5): 956–963, doi: 10.1016/j.bbmt.2017.12.785, indexed in Pubmed: 29274396.
  74. Wedge E, Sengeløv H, Hansen JW, et al. Improved outcomes after allogenic hematopoietic stem cell transplantation with fludarabine/treosulfan for patients with myelodysplastic syndromes. Biol Blood Marrow Transplant. 2020; 26(6): 1091–1098, doi: 10.1016/j.bbmt.2020.02.010, indexed in Pubmed: 32088368.
  75. Bazarbachi A, Schmid C, Labopin M, et al. Evaluation of trends and prognosis over time in patients with AML relapsing after allogeneic hematopoietic cell transplant reveals improved survival for young patients in recent years. Clin Cancer Res. 2020; 26(24): 6475–6482, doi: 10.1158/1078-0432.CCR-20-3134, indexed in Pubmed: 32988970.
  76. Rautenberg C, Bergmann A, Germing U, et al. Prediction of response and survival following treatment with azacitidine for relapse of acute myeloid leukemia and myelodysplastic syndromes after allogeneic hematopoietic stem cell transplantation. Cancers (Basel). 2020; 12(8): 2255, doi: 10.3390/cancers12082255, indexed in Pubmed: 32806572.
  77. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018; 131(12): 1275–1291, doi: 10.1182/blood-2017-09-801498, indexed in Pubmed: 29330221.
  78. Terwijn M, van Putten WLJ, Kelder A, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol. 2013; 31(31): 3889–3897, doi: 10.1200/JCO.2012.45.9628, indexed in Pubmed: 24062400.
  79. Czyz A, Nagler A. The role of measurable residual disease (MRD) in hematopoietic stem cell transplantation for hematological malignancies focusing on acute leukemia. Int J Mol Sci. 2019; 20(21), doi: 10.3390/ijms20215362, indexed in Pubmed: 31661875.
  80. Tsirigotis P, Byrne M, Schmid C, et al. Relapse of AML after hematopoietic stem cell transplantation: methods of monitoring and preventive strategies. A review from the ALWP of the EBMT. Bone Marrow Transplant. 2016; 51(11): 1431–1438, doi: 10.1038/bmt.2016.167, indexed in Pubmed: 27295272.
  81. Lion T, Watzinger F, Preuner S, et al. The EuroChimerism concept for a standardized approach to chimerism analysis after allogeneic stem cell transplantation. Leukemia. 2012; 26(8): 1821–1828, doi: 10.1038/leu.2012.66, indexed in Pubmed: 22395360.
  82. Quek L, Ferguson P, Metzner M, et al. Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia. Blood Adv. 2016; 1(3): 193–204, doi: 10.1182/bloodadvances.2016000760, indexed in Pubmed: 29296935.
  83. Steinmann J, Bertz H, Wäsch R, et al. 5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft. Bone Marrow Transplant. 2015; 50(5): 690–695, doi: 10.1038/bmt.2015.10, indexed in Pubmed: 25774594.
  84. Schroeder T, Rachlis E, Bug G, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions — a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol. Blood Marrow Transplan. 2015; 21(4): 653–660, doi: 10.1016/j.bbmt.2014.12.016.
  85. Greiner J, Götz M, Bunjes D, et al. Immunological and clinical impact of manipulated and unmanipulated DLI after allogeneic stem cell transplantation of AML patients. J Clin Med. 2019; 9(1), doi: 10.3390/jcm9010039, indexed in Pubmed: 31878060.
  86. DeFilipp Z, Chen YB. Strategies and challenges for pharmacological maintenance therapies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016; 22(12): 2134–2140, doi: 10.1016/j.bbmt.2016.08.021, indexed in Pubmed: 27567491.
  87. Schroeder T, Rautenberg C, Haas R, et al. Hypomethylating agents after allogeneic blood stem cell transplantation. Stem Cell Investig. 2016; 3: 84, doi: 10.21037/sci.2016.11.04, indexed in Pubmed: 28066786.
  88. Oran B, Lima Mde, Garcia-Manero G, et al. A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients. Blood Adv. 2020; 4(21): 5580–5588, doi: 10.1182/bloodadvances.2020002544.
  89. Craddock C, Labopin M, Robin M, et al. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2016; 101(7): 879–883, doi: 10.3324/haematol.2015.140996.
  90. Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia. 2012; 26(3): 381–389, doi: 10.1038/leu.2011.234, indexed in Pubmed: 21886171.
  91. Schmid C, Labopin M, Nagler A, et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. Journal of Clinical Oncology. 2007; 25(31): 4938–4945, doi: 10.1200/jco.2007.11.6053.
  92. Schroeder T, Rautenberg C, Haas R, et al. Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation. Int J Hematol. 2018; 107(2): 138–150, doi: 10.1007/s12185-017-2364-4, indexed in Pubmed: 29143282.
  93. Durrani J, Maciejewski J. Idiopathic aplastic anemia vs hypocellular myelodysplastic syndrome. Hematology. 2019; 2019(1): 97–104, doi: 10.1182/hematology.2019000019, indexed in Pubmed: 31808900.
  94. Bono E, McLornan D, Travaglino E, et al. Clinical, histopathological and molecular characterization of hypoplastic myelodysplastic syndrome. Leukemia. 2019; 33(10): 2495–2505, doi: 10.1038/s41375-019-0457-1, indexed in Pubmed: 30940907.
  95. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20): 2375–2390, doi: 10.1182/blood-2016-01-643569, indexed in Pubmed: 26980727.
  96. Melody M, Al Ali N, Zhang L, et al. Decoding bone marrow fibrosis in myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk. 2020; 20(5): 324–328, doi: 10.1016/j.clml.2020.01.003, indexed in Pubmed: 32044274.
  97. Zahr AA, Salama ME, Carreau N, et al. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies. Haematologica. 2016; 101(6): 660–671, doi: 10.3324/haematol.2015.141283, indexed in Pubmed: 27252511.
  98. Kröger N, Zabelina T, van Biezen A, et al. MDS Subcommittee of the Chronic Leukemia Working Party (CLWP) of the European Group for Blood and Marrow Transplantation (EBMT). Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis. Haematologica. 2011; 96(2): 291–297, doi: 10.3324/haematol.2010.031229, indexed in Pubmed: 20971823.
  99. Candelaria M, Dueñas-Gonzalez A. Therapy-related myelodysplastic syndrome. Expert Opin Drug Saf. 2015; 14(5): 655–665, doi: 10.1517/14740338.2015.1014340, indexed in Pubmed: 25675961.
  100. Bhatia S. Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol. 2013; 40(6): 666–675, doi: 10.1053/j.seminoncol.2013.09.013, indexed in Pubmed: 24331189.
  101. Quintás-Cardama A, Daver N, Kim H, et al. A prognostic model of therapy-related myelodysplastic syndrome for predicting survival and transformation to acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2014; 14(5): 401–410, doi: 10.1016/j.clml.2014.03.001, indexed in Pubmed: 24875590.
  102. Fianchi L, Criscuolo M, Fabiani E, et al. Therapy-related myeloid neoplasms: clinical perspectives. Onco Targets Ther. 2018; 11: 5909–5915, doi: 10.2147/OTT.S101333.
  103. Caira M, Latagliata R, Girmenia C. The risk of infections in patients with myelodysplastic syndromes in 2016. Expert Rev Hematol. 2016; 9(6): 607–614, doi: 10.1080/17474086.2016.1181540, indexed in Pubmed: 27100058.
  104. Goldberg SL, Chen Er, Corral M, et al. Incidence and clinical complications of myelodysplastic syndromes among United States Medicare beneficiaries. J Clin Oncol. 2010; 28(17): 2847–2852, doi: 10.1200/JCO.2009.25.2395, indexed in Pubmed: 20421543.
  105. Sullivan LR, Sekeres MA, Shrestha NK, et al. Epidemiology and risk factors for infections in myelodysplastic syndromes. Transpl Infect Dis. 2013; 15(6): 652–657, doi: 10.1111/tid.12130, indexed in Pubmed: 24010918.
  106. Gil L. [Infectious complication after allogeneic stem cell transplantation] [Article in Polish]. Acta Haematol Pol. 2010; 41(3): 363–370.
  107. Dayyani F, Conley AP, Strom SS, et al. Cause of death in patients with lower-risk myelodysplastic syndrome. Cancer. 2010; 116(9): 2174–2179, doi: 10.1002/cncr.24984, indexed in Pubmed: 20162709.
  108. Mądry K, Lis K, Biecek P, et al. Predictive model for infection risk in myelodysplastic syndromes, acute myeloid leukemia, and chronic myelomonocytic leukemia patients treated with azacitidine; azacitidine infection risk model: the Polish Adult Leukemia Group Study. Clin Lymphoma Myeloma Leuk. 2019; 19(5): 264–274.e4, doi: 10.1016/j.clml.2019.01.002, indexed in Pubmed: 30898482.
  109. Latagliata R, Niscola P, Fianchi L, et al. Pulmonary infections in patients with myelodysplastic syndromes receiving frontline azacytidine treatment. Hematol Oncol. 2020; 38(2): 189–196, doi: 10.1002/hon.2710.
  110. Musto P, Maurillo L, Spagnoli A, et al. Ad Hoc Italian Cooperative Study Group on Azacitidine in Myelodysplastic Syndromes Acute Leukemias. Azacitidine for the treatment of lower risk myelodysplastic syndromes : a retrospective study of 74 patients enrolled in an Italian named patient program. Cancer. 2010; 116(6): 1485–1494, doi: 10.1002/cncr.24894, indexed in Pubmed: 20151429.
  111. Schuck A, Goette MC, Neukirchen J, et al. A retrospective study evaluating the impact of infectious complications during azacitidine treatment. Ann Hematol. 2017; 96(7): 1097–1104, doi: 10.1007/s00277-017-3001-2, indexed in Pubmed: 28474144.
  112. Mossuto S, Attardi E, Alesiani F, et al. SARS-CoV-2 in myelodysplastic syndromes: a snapshot from early Italian experience. Hemasphere. 2020; 4(5): e483, doi: 10.1097/HS9.0000000000000483, indexed in Pubmed: 33062948.
  113. Toma A, Fenaux P, Dreyfus F, et al. Infections in myelodysplastic syndromes. Haematologica. 2012; 97(10): 1459–1470, doi: 10.3324/haematol.2012.063420.
  114. Lee JH, Lee KH, Lee JH, et al. Decreased incidence of febrile episodes with antibiotic prophylaxis in the treatment of decitabine for myelodysplastic syndrome. Leuk Res. 2011; 35(4): 499–503, doi: 10.1016/j.leukres.2010.07.006, indexed in Pubmed: 20674021.
  115. Pomares H, Arnan M, Sánchez-Ortega I, et al. Invasive fungal infections in AML/MDS patients treated with azacitidine: a risk worth considering antifungal prophylaxis? Mycoses. 2016; 59(8): 516–519, doi: 10.1111/myc.12500, indexed in Pubmed: 27027972.
  116. Platzbecker U, Fenaux P, Steensma D, et al. Imerge: a phase 3 study to evaluate imetelstat in transfusion-dependent subjects with IPSS low or intermediate-1 risk myelodysplastic syndromes (MDS) that is relapsed/refractory to erythropoiesis-stimulating agent (ESA) treatment. Blood. 2020; 136(Supplement 1): 17–17, doi: 10.1182/blood-2020-138810.
  117. Henry DH, Glaspy J, Harrup R, et al. Oral roxadustat demonstrates efficacy in anemia secondary to lower-risk myelodysplastic syndrome irrespective of ring sideroblasts and baseline erythropoietin levels. Blood. 2020; 136(Suppl 1): 29–30, doi: 10.1182/blood-2020-142499.
  118. Garcia JS, Wei A, Borate U, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study. Blood. 2020; 136(Supplement 1): 55–57, doi: 10.1182/blood-2020-139492.
  119. Zeidan MA, Pollyea DA, Garcia JC, et al. 3109 a phase 1b study evaluating the safety and efficacy of venetoclax in combination with azacitidine for the treatment of relapsed/refractory myelodysplastic syndrome. 62nd ASH Annual Meeting and Exposition 2020. https://ash.confex.com/ash/2020/webprogram/Paper136413.html (October 18, 2021).
  120. Moyo TK, Watts J, Skikne B, et al. Preliminary results from a phase II study of the combination of pevonedistat and azacitidine in the treatment of MDS and MDS/MPN after failure of DNA methyltransferase inhibition. Blood. 2019; 134(Suppl_1): 4236–4236, doi: 10.1182/blood-2019-130003.
  121. Sekeres MA, Watts JM, Radinoff A, et al. 653 Efficacy and safety of pevonedistat plus azacitidine vs azacitidine alone in higher-risk myelodysplastic syndromes (MDS) from Study P-2001 (NCT02610777) . https://ash.confex.com/ash/2020/webprogram/Paper135840.html (October 18, 2021).
  122. Sallman DA, Asch AS, Al Malki MM, et al. The first-in-class anti-CD47 antibody magrolimab (5F9) in combination with azacitidine is effective in MDS and AML patients: ongoing phase 1b results. Blood. 2019; 134(Suppl_1): 569–569, doi: 10.1182/blood-2019-126271.
  123. Sallman DA, DeZern A, Garcia-Manero G, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2021; 39(14): 1584–1594, doi: 10.1200/jco.20.02341.
  124. Navada SC, Garcia-Manero G, Atallah E, et al. Phase II study of oral rigosertib combined with azacitidine (AZA) as first line therapy in patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS). Blood. 2019; 134(Suppl_1): 566–566, doi: 10.1182/blood-2019-131676.