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Therapeutic options for MDS, approved by EMA or part of standard care

Please click on a heading to expand information on that therapy. 

Transfusion therapy

Transfusion therapy

Red cell transfusion

  • Red cell transfusion is the most widely used active therapy for MDS patients
  • Red cell transfusion for severe anaemia is usually symptomatically beneficial but is associated with established risks
  • Available evidence for the use of red cell transfusion in MDS is limited

Evidence that red cell transfusion is efficacious in MDS

  • No randomised controlled trials are available, for clear ethical reasons
  • Symptomatic anaemia produces a decrement in quality of life (QoL)1,2,3,4
  • Severe anaemia can be life threatening due to cardiac compromise particularly in an older patient population such as MDS1
  • Red cell transfusion is associated with symptomatic benefit in most patients
  • Cohort studies demonstrate a relationship between haemoglobin concentration and HRQoL1,2,3

Safety of red cell transfusion in MDS

  • Red cell transfusions are administered repeatedly and frequently in MDS patients, with recurrent exposure to multiple donors.
  • Acute adverse effects of red cell transfusion in MDS include:
    • simple transfusion reactions
    • circulatory overload
    • transfusion associated lung injury
    • transfusion of incompatible red cell units
  • Adverse effects of recurrent red cell transfusion include
    • red cell alloimmunisation
    • transfusional iron overload
  • There is no evidence that red cell transfusion promotes disease progression in MDS patients

Practice guidelines for red cell transfusion

1. Haemoglobin thresholds / transfusion triggers
  • No high quality evidence is available to determine optimal haemoglobin concentration thresholds for red cell transfusion
  • Extrapolation of RCT data from critical care and other acute emergency settings is inappropriate although appears to be widely contended (ref)
  • Continuous individual evaluation of symptoms and degree of anemia is recommended
  • Most cohort studies report a ‘restrictive’ Hb threshold typically either <80 g/L with variation from <70 - <90 g/L5,6
  • Best practice currently individualises haemoglobin thresholds based on a combination of:
    • patient co-morbidities
    • patient symptoms at a given Hb concentration
    • observed symptomatic benefit from previous transfusion episodes
    • patient preference
  • No consistent single haemoglobin threshold trigger can be recommended
  • Red cell transfusion is strongly recommended at <70 g/L as anaemia is always symptomatic.
  • Recommendation levels: grade B, level 1-
2. Haemoglobin target values
  • No high quality evidence is available
  • Cohort studies have typically reported target Hb values of 90-100 g/L
  • A cohort clinical trial to achieve a target of >120 g/L  with either ESA (darbepoietin alfa) or red cell transfusion demonstrated an improvement in HRQoL with maintenance at the target Hb compared to lower Hb values in the same patient irrespective of the treatment modality used.7
  • Best practice should individualise a target haemoglobin value based on a combination of patient co-morbidities (cardiac, respiratory), symptoms at a given Hb concentration, observed symptomatic benefit from a (series of) transfusion episodes and patient preference
  • No consistent single haemoglobin target value can be recommended
  • Recommendation level: grade C, level 2-
3. Transfusion frequency
  • No high quality evidence is available
  • Most transfusion-dependent patients require regular and frequent red cell transfusion
  • Transfusion intensity is often increased over time
  • The number of units transfused at each transfusion episode depends on:
    • the target haemoglobin value, determined for sustained symptomatic benefit
    • practical issues (e.g. day case unit capacity)
    • patient preference.
  • There need be no limit to the frequency nor to total number of units transfused during an MDS patient’s lifetime; this should be driven by clinical symptomatic benefit
  • If transfusion frequency and number of units per transfusion episode is steadily increasing, consideration should be given to other causes of anaemia (e.g. Bleeding, haemolysis, haematinic deficiency) or to MDS disease progression
  • Transfusion frequency should reflect the duration of symptomatic benefit between transfusion episodes
  • Transfusion should be considered for symptomatic anaemia prior to interventional / surgical procedures or active infection
  • Recommendation level: grade C, level 2- (for all recommendations)
4. Prophylactic red cell antigen matching
  • Red cell alloimmunisation occurs in to 10-30% chronically transfused MDS patients with increasing frequency proportional to total transfusion burden.8,9
  • Prophylactic red cell antigen matching (principally Rh and K) may reduce the incidence of red cell alloimmunisation for the matched antigens but the clinical benefit of this remains unclear
  • routine red cell antigen matching cannot currently be recommended for all chronically transfused MDS patients
  • Recommendation level: grade C, level 2-
5. Symptomatic benefit versus toxicity
  • The risks and the benefits of a chronic red cell transfusion should be discussed with patients who have symptomatic anaemia
  • The decision to prioritise symptomatic benefit with improved QoL over potential long-term toxicity seems most logical and evidence-based
  • Transfusion episode frequency, and number of units transfused at each transfusion episode should reflect the duration of symptomatic benefit from each transfusion episode, and should not be over-ridden by concerns about potential long-term toxicity given the current evidence base for long-term toxicity.
  • Recommendation level: grade C, level 2- (for all)


  1. Oliva et al, Leuk Res 2005
  2. Pinchon et al, Am J Haem 2009
  3. Jansen et al, BJH 2003
  4. Stauder R, et al. Leukemia. 2018 Jun;32(6):1380-1392
  5. Gu, Estcourt et al, Cochrane meta-analysis 2015
  6. McQuilten et al, 2017
  7. Nilsson-Ehle et al, Eur J Haem, 2011
  8. Rozovski, Isr Med Assoc J, 2015
  9. Lin et al, Vox Sang, 2017
  10. Malcovati et al, JCO, 2007
  11. Goldberg et al, JCO 2010

Platelet transfusion

There is an absence of evidence to inform recommendations for platelet transfusion in persistent severe thrombocytopenia in patients with MDS receiving supportive care only1

  • In patients receiving chemotherapy (intensive chemotherapy, low dose chemotherapy or HMA): transfuse platelets per institutional guidance
  • In MDS with persistent severe thrombocytopenia receiving supportive care only, prophylactic platelet transfusion cannot be routinely recommended if there is no active bleeding, but should be considered in patients with bleeding.
  • In patients with bleeding, anti-fibrinolytic agents such as tranexamic acid should also be considered


  1. Malouf et al, Cochrane Database Syst Rev. ; 5: CD012342. doi:10.1002/14651858.CD012342.pub2, 2018.

Granulocyte transfusion

  • There is no evidence that granulocyte transfusions can improve clinical outcomes in MDS patients. As such no recommendation can be made regarding their use in the management of MDS.

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Chelation therapy

Iron overload

  • Transfusion dependency (TD) inevitably results in iron overload after 20-25 units
  • There is limited evidence that iron overload produces clinically relevant organ damage in heart and liver and may affect erythropoiesis
  • Raised serum ferritin correlates with reduced survival
  • Raised serum ferritin and elevated labile plasma iron correlate with poorer outcomes in stem cell transplant (SCT)
  • Patients with MDS and ring sideroblasts may have iron overload even without TD

Choice of iron chelator

  • Deferoxamine has the longest safety and efficacy evidence but in older patients tolerance and practical administration difficulties may limit usage
  • Deferasirox is licensed for patients in whom deferoxamine is contraindicated or inadequate
  • Deferiprone should be considered if neither deferoxamine or deferasirox are appropriate and ANC > 1.5 x 109/L

Benefits of chelation therapy

  • Retrospective studies suggest survival benefit for iron chelation in transfusion dependent lower risk MDS patients
  • Retrospective evidence of improvement in organ function with chelation
  • Single arm observational studies suggest survival benefit of chelation pre-SCT
Hematological improvement with Deferasirox
  • In vitro evidence of negative impact of iron on hematopoiesis
  • Hematological improvement observed in a variable proportion patients with MDS

Monitoring iron chelation therapy (efficacy)

  • No evidence-based recommendations can be given for tests to monitor efficacy of iron chelation therapy
  • Serum ferritin is most widely used but the target serum ferritin cannot be defined
  • In the absence of a clear correlation between MRI T2* liver / cardiac iron content and clinical outcome, this modality cannot be routinely recommended for monitoring
  • The goal of therapy should be to at least stabilize ferritin, ideally reduce it
  • Chelation should be interrupted if serum ferritin falls into the normal range

Iron chelation should be considered for:

  • Lower risk IPSS, red cell transfusion dependent MDS, defined as WHO 2016 MDS with single or multi-lineage dysplasia, MDS with ring sideroblasts, and MDS with isolated del(5q), and/or IPSS Low or INT-1,
    • and a serum ferritin level higher than 1000 ng/mL after approximately 25 units of red cells
    • in the absence of patient-related (non-MDS) factors anticipated to reduce life expectancy to < 3 years (recommendation level C)
  • MDS patients with iron overload who are transplant candidates, irrespective of IPSS risk score


  • Malcovati L, Hellstrom-Lindberg E, Bowen D, Ades L, Cermak J, Del Canizo C, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013 Oct 24;122(17):2943-64.
  • Fenaux P, Rose C. Impact of iron overload in myelodysplastic syndromes. Blood Rev. 2009 Dec;23 Suppl 1:S15-9.
  • Giagounidis A, Leto di Priolo S, Ille S, Fenaux P. A European survey on the detection and management of iron overload in transfusion-dependent patients with MDS. Ann Hematol. 2011 Jun;90(6):667-73.
  • Leitch HA. Optimizing therapy for iron overload in the myelodysplastic syndromes: recent developments. Drugs. 2011 Jan 22;71(2):155-77.
  • Angelucci E, Cianciulli P, Finelli C, Mecucci C, Voso MT, Tura S. Unraveling the mechanisms behind iron overload and ineffective hematopoiesis in myelodysplastic syndromes. Leuk Res. 2017 Nov;62:108-15.
  • Cermak J, Jonasova A, Vondrakova J, Walterova L, Hochova I, Siskova M, et al. Efficacy and safety of administration of oral iron chelator deferiprone in patients with early myelodysplastic syndrome. Hemoglobin. 2011;35(3):217-27.
  • de Montalembert M, Ribeil JA, Brousse V, Guerci-Bresler A, Stamatoullas A, Vannier JP, et al. Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome. PLoS One. 2017;12(3):e0172147.
  • Gattermann N, Coll R, Jacobasch L, Allameddine A, Azmon A, DeBonnett L, et al. Effect of deferasirox + erythropoietin vs erythropoietin on erythroid response in Low/Int-1-risk MDS patients: Results of the phase II KALLISTO trial. Eur J Haematol. 2018 May 19.
  • Platzbecker U, Bornhauser M, Germing U, Stumpf J, Scott BL, Kroger N, et al. Red blood cell transfusion dependence and outcome after allogeneic peripheral blood stem cell transplantation in patients with de novo myelodysplastic syndrome (MDS). Biol Blood Marrow Transplant. 2008 Nov;14(11):1217-25.
  • Armand P, Sainvil MM, Kim HT, Rhodes J, Cutler C, Ho VT, et al. Pre-transplantation iron chelation in patients with MDS or acute leukemia and iron overload undergoing myeloablative allo-SCT. Bone Marrow Transplant. 2013 Jan;48(1):146-7.

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Erythropoiesis-stimulating factors (ESA)

Erythropoiesis-stimulating factors (ESA)


  • ESAs encompass erythropoietin alpha or beta, generic epoetins, and darbepoetin. Choice of compound can follow national or local guidelines.
  • Treatment with ESAs may improve hemoglobin levels and abrogate transfusion need in lower-risk MDS. Response rates varies between 23-75%, depending on patient selection
  • A recent prospective randomized trial confirmed a superior efficacy of epoetin alpha compared to placebo; 45.9 vs 4.4% (p<0.001).
  • Addition of Granulocyte-CSF (G-CSF) can induce responses in ESA refractory patients.
  • Retrospective studies show a survival benefit for patients treated with EPO±G-CSF compared to untreated patients, with no impact on AML transformation.
  • The prospective EU MDS Registry data study showed a borderline survival benefit for lower-risk MDS treated with ESA (p=0.07) and that ESA treatment, given before or early after onset of transfusion need, significantly prolongs time to onset of a permanent transfusion need.

Decision models for treatment with EPO±G-CSF

  • Older decision models are based on studies in which many patients had long-standing transfusion-dependent anemia and sometimes higher risk scores than IPSS low and intermediate-1 risk.
  • Treatment efficacy is higher in recent studies enrolling patients before or early after the onset of transfusion need. Therefore, older decision models have been substituted with the following recommendations:
  • Based on recent studies, it is recommended to if possible start treatment before onset of transfusion need.
  • The response to treatment is expected to be less favourable in patients with:
    • S-EPO levels >100 U/L
    • Transfusion who need higher than 2 units / 4 weeks
    • Higher IPSS and IPSS-R risk scores
  • ESA treatment is not recommended in patients with S-Epo >500 U/L + transfusion intensity ≥ 2 units / 4 weeks
  • ESA treatment in potential candidates for SCT should not delay the SCT process

Indication for treatment

  • IPSS-R very low, low or intermediate risk MDS
  • Symptomatic anemia (patient-reported symptoms)
  • Transfusion-dependent anemia, irrespective of symptoms
  • The hemoglobin level required to start treatment must be evaluated individually, and with consideration of co-morbid conditions.
  • Patients should preferably be treated before the onset of a permanent transfusion need.

Erythroid response criteria

For treatment outside clinical trials, the criteria used in publications from the French and Nordic MDS groups are recommended.

Partial  erythroid response (PER)
  • In transfusion-dependent patients:  Stable anemia without need for transfusions
  • In patients with stable anemia: Absolute increase of hemoglobin by  ≥15 g/L
Complete erythroid response (CER):
  •   Stable hemoglobin ≥115 g/L

For treatment within clinical trials, the IWG 2018 criteria should be used.

Treatment, general aspects

  • Start with ESA lower dose for 8 weeks. If no response (at least PER):
  • Increase ESA to max dose for 8 weeks.  If no response (at least PER):
  • Consider to add  G-CSF for 8 weeks. If not ≥ PER after 8 weeks on combined ESA + G-CSF, terminate treatment.
  • Check S-ferritin regularly. If the value drops below the upper limit of the normal range, consider oral iron replacement therapy.

Erythropoietin dosing

Induction phase

  • Start with Epo 30 000 - 40 000U sc once weekly.  Increase to 60 000 / week (divided over one or two doses) if no response after 8 weeks.
  • If no response after 8 weeks on maximum dose, consider addition of G-CSF.
  • Weekly monitoring of CBC during first 8 weeks to detect rapid increase of Hb >12 g/dL.
  • The starting dose in low weight patients with stable anemia, and always in case of reduced renal function should be lower than 30 000 U/week
  • Doses >60 000 U/week is not supported by scientific evidence.

Maintenance phase

  • In case of CER with Hb 12 - 13 g/dL for more than 8 weeks, decrease Epo dose. Interval could either be increased to up to 14 days or the dose / injection could be reduced.
  • Median maintenance dose in published studies is 30 000 U / week (range 5-60 000), higher for MDS with ring sideroblasts (MDS-RS).


  • If Hb above upper normal range, interrupt Epo treatment and restart at 50% of dose when Hb decreases below approximately 12 g/dL.
  • Consider venesectio if Hb levels above upper normal range and if increase has been rapid.

Darbepoetin dosing

Induction phase

  • Start with 300 µg/14 d (or 150 µg/week. Maximum dose 300 µg/week.
  • The starting dose in low weight patients with stable anemia, and always in case of reduced renal function should be lower.

Maintenance phase

  • Limited experience, DA 300 µg / 1-3 weeks. Prolong interval between injections rather than reducing dose/injection


  • See Epo. Darbepoetin may lead to a more long-lasting hemoglobin rise than EPO.
  • Considering the longer half-life; venesectio may be considered if supranormal Hb levels.

G-CSF dosing

  • Clinical experience suggests 1-2 weekly doses.
  • Start with 300 µg once weekly, alternatively 120 µg 2-3 times / week.
  • Treatment should aim at a clear rise in neutrophil count. If no response, increase the dose to a maximum of 300 µg x 3/week.
  • In case of high neutrophil counts, reduce the number of injections/week, then reduce dose / injection
  • Long-acting G-CSF has not been evaluated in MDS and cannot be recommended.

Management of patients in case of a loss of response

  • No published evidence, these guidelines are based on clinical experience
  • If no signs of disease progression other than anemia , increase doses of ESA + G-CSF, if these are lower than maximal. Do not treat with maximum doses for more than 16 weeks.
  • Loss of  response is generally not associated with disease progression, but a new BM examination and risk evaluation are recommended in all patients in whom disease-modifying treatment including stem cell transplantation would be considered in case of disease progression. 

Recommendation levels

Recommendation Epo
  • Recommendation grade A, evidence level Ia
Recommendation Epo + G-CSF
  • Recommendation grade A, evidence level Ib.
Recommendation DA±G-CSF
  • Recommendation grade B, evidence level IIa.


  • Hellstrom-Lindberg E, et al.. Br J Haematol. 2003;120:1037-46
  • Houston BL, Ann Hematol. 2017 Dec;96(12):2025-2029.
  • Park S, et al. Blood. 2008 Jan 15;111(2):574-82.
  • Jädersten M, et al.. J Clin Oncol. 2008 Jul 20;26(21):3607-13.
  • Park S. et al Br J Haematol. 2016 Sep;174(5):730-47. (DA)
  • Park S, et al Br J Haematol. 2018 Dec 13. doi: 10.1111/bjh.15707.
  • Garelius HK, et al. J Intern Med. 2017 Mar;281(3):284-299.
  • Fenaux P, et al. Leukemia. 2018 Dec;32(12):2648-2658.
  • Platzbecker U, et al. Blood. 2018 Nov 7. pii: blood-2018-06-857102.

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Immunosuppressive treatment (IST)

Immunosuppressive treatment (IST)


  • Treatment with immunosuppressive agents (IST) such as ATG and CSA may improve cytopenia and abrogate transfusion need in IPSS-R low - intermediate risk MDS with hypoplastic to normocellular BM
  •  Response types vary from single-lineage recovery to complete trilineage response.
  • This strongly suggests an immune pathogenesis  in subgroups of lower-risk MDS and underscores the role of T lymphocytes in the aberrant immune reactivity.

Indication for treatment

  • Hypoplastic (hypocellular) or normocellular MDS without secondary marrow fibrosis
  • IPSS-R very low/low/intermediate
  • Normal karyotype with the exception of trisomy 8
  • Symptomatic anemia and/or trombocytopenia/neutropenia. These cytopenias usually develop rapidly and become severe.
  • The degree of cytopenia required to start treatment must be evaluated individually, and with consideration of co-morbid conditions

Decision model for treatment with immunosuppressive agents (ATG/CSA)

  • Age < 60y (ATG and CSA) (no evidence for exact cut-off)
  • Age > 60 y (CSA only) (no evidence for exact cut-off)
  • HLA-DR-15 genotype may support a response
  • Presence of PNH clone may support a response

Hematological response

  • Responses are assessed according to IWG 2006
  • Responses may be stable, durations >10 years are reported
  • Important! Responses may be late and not be clinically obvious until 6-8 months after ATG

ATG + CSA treatment 

important general notes

  • Highly specialised treatment with significant adverse events. Should only be used in departments with experience of the treatment and accessibility of complex care of patients
  • The department should have an established local protocol for ATG treatment
  • PJP and HZV prophylaxis for 1 year according to local protocols
  • Selective gastrointestinal decontamination according to local protocols
  • No indication for use of G-CSF and TPO-agonist outside clinical trials
  • If progressive disease after 3-6 months or no response after 6-8 months consider allogenic cell transplanatation


  • ATGThere are different ATG products available, and ATG should be used according to local traditions/experience:
    • Horse ATG, Genzyme (LymphoglobulineTM); 15 mg/kg, d 1-5  
    • Rabbit ATG, Genzyme (ThymoglobulineTM); 3.75 mg/kg d. 1-5
    • Rabbit ATG, Fresenius (ATG-FreseniusTM); 20 mg/kg, d. 1-3
    • Horse ATG, Pfizer (ATGAMTM); 40 mg/kg, d 1-4
  • Prednisolon 1 mg/kg/day during day 1-14, taper to zero during day 15-28
    • Observe for serum sickness: rash, arthalgia/arthritis and fever
  • Cyclosporin A (CSA) oral 2 x 3 mg/kg = 6 mg/kg/day day 1-180
    • Usually dose reduction due to adverse events (creatinine raise, tremor)
    • If no response after 8 months stop CSA or if minimal response continue up to 12 months. The treatment should be slowly tapered.

Recommendation levels  IST in MDS

Recommendation ATG + CSA in hypoplastic MDS
  • Recommendation grade A, evidence level Ib


  • Aggarwal S, van de Loosdrecht AA, Alhan C, Ossenkoppele GJ, Westers TM, Bontkes HJ. Role of immune responses in the pathogenesis of low-risk MDS and high-risk MDS: implications for immunotherapy. Br J Haematol 2011;153(5):568-581.
  • Kadia TM, Borthakur G, Garcia-Manero G, Faderl S, Jabbour E, Estrov Z, York S, Huang X, Pierce S, Brandt M, Koller C, Kantarjian HM, Ravandi F. Final results of the phase II study of rabbit anti-thymocyte globulin, ciclosporin, methylprednisone, and granulocyte colony-stimulating factor in patients with aplastic anaemia and myelodysplastic syndrome. Br J Haematol 2012;157(3):312-320
  • Passweg JR, Giagounidis AA, Simcock M, Aul C, Dobbelstein C, Stadler M, Ossenkoppele G, Hofmann WK, Schilling K, Tichelli A, Ganser A. Immunosuppressive therapy for patients with myelodysplastic syndrome: a prospective randomized multicenter phase III trial comparing antithymocyte globulin plus cyclosporine with best supportive care--SAKK 33/99. J Clin Oncol 2011;29(3):303-309
  • Stahl, M.;  DeVeaux, M.;  de Witte, T.;  Neukirchen, J.;  Sekeres, M. A.;  Brunner, A. M.;  Roboz, G. J.;  Steensma, D. P.;  Bhatt, V. R.;  Platzbecker, U.;  Cluzeau, T.;  Prata, P. H.;  Itzykson, R.;  Fenaux, P.;  Fathi, A. T.;  Smith, A.;  Germing, U.;  Ritchie, E. K.;  Verma, V.;  Nazha, A.;  Maciejewski, J. P.;  Podoltsev, N. A.;  Prebet, T.;  Santini, V.;  Gore, S. D.;  Komrokji, R. S.; Zeidan, A. M., 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.
  • Stadler M et al: A prospective, randomized, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia. 2004 Mar;18(3):460-5. Addressing horse vs rabbit in MDS.

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Lenalidomide for lower-risk del(5q) MDS

Lenalidomide for lower-risk del(5q) MDS

Indication for treatment

  • IPSS-R very low - intermediate risk MDS with
    • transfusion dependent anemia
    • ESA failure or ineligible for ESA
    • del(5q) without additional chromosomal abnormalities or one additional chromosomal abnormality not involving chr 7 or 17 *
    • without excess of blasts
    • Clinical trial data shows response rates in this group of patients are:
      • 56% transfusion independence
      • 50% cytogenetic response
      • prolonged survival in patients obtaining a response
  • Reasons to consider not to treat with lenalidomide
    • TP53 mutations / IHC +
      • Patient candidate to allogeneic SCT
      • Patient candidate to modifier drugs (HMA) careful discussion of risks and benefit is required
    • Risk assessment indicating upfront allo SCT
    • Consider NGS analysis before treatment in patients potentially eligible for SCT in case of clonal progression

Response criteria

  • Response is assessed according to IWG
  • Response to lenalidomide is usually detected early, within 4-6 weeks

Treatment - general aspects

  • Starting dose 10 mg/d for in cycles of 21/28 days.
  • Upfront dose reduction to 5 mg/day continuous treatment may be indicated in elderly / fragile patients with pre-existing neutropenia or thrombocytopenia and/or bone marrow fibrosis
  • Further reductions and supportive care with G-CSF may be indicated if treatment induced grade 4 cytopenia
  • Thromboprophylaxis not generally recommended:
    • Adjust according to individual risk (previous DVT, other risk factors)

Lenalidomide-specific follow-up  during treatment

  • Clinical follow-up for infections, and skin and allergic reactions
  • Blood counts
    • Note: deep cytopenia can develop rapidly and cause serious infections
    • Weekly full hematology incl WBC differential and reticulocyte count for 8-12 weeks
    • Every month after the initiation of response and during response
    • If no response: clinical judgement
  • Bone Marrow (morphology and cytogenetics; NGS recommended)
    • After 3-4 cycles irrespective of hematological response
    • Every 6-12 months during response
    • In case of loss of response or signs of progression
  • Other blood tests every 3 months; TSH, S-Mg

Management of patients in case of lost response

  • No published evidence, these guidelines are based on clinical experience.
  • Lost response may or may not be associated with overt disease progression but usually with recurrence of del(5q) clone
  • Recommended investigations
    • BM morphology, cytogenetics, and biopsy with p53 immunohistochemistry
    • NGS analysis strongly recommended
  • Clinical management:
    • RBC transfusions and oral chelation as needed
    • If no progression, retreatment with Len after a “wash-out” period or retreatment with ESA may be considered
    • If progression, manage as a higher risk MDS including potential SCT.
    • If clonal progression during maintained response: discuss with specialist
Recommendation levels
  • IPSS low and INT-1 risk MDS with isolated del(5q), transfusion dependency
    • Recommendation level A
  • IPSS low and INT-1 risk MDS with del(5q) and one additional chromosomal abnormality not involving chr 7 or 17, transfusion dependency
    • Recommendation level A


  • List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006 Oct 5;355(14):1456-65.
  • Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, et al. 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 Oct 6;118(14):3765-76.
  • 3.  Stahl M, Zeidan AM. Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications. Cancer. 2017 May 15;123(10):1703-13.
  • List AF, Bennett JM, Sekeres MA, Skikne B, Fu T, Shammo JM, et al. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. Leukemia. 2014 May;28(5):1033-40.
  • Giagounidis A, Fenaux P, Mufti GJ, Muus P, Platzbecker U, Sanz G, et al. Practical recommendations on the use of lenalidomide in the management of myelodysplastic syndromes. Ann Hematol. 2008 May;87(5):345-52.
  • Jadersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Gohring G, et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011 May 20;29(15):1971-9.

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Luspatercept for lower-risk MDS with ring sideroblasts

Luspatercept for lower-risk MDS with ring sideroblasts

Luspatercept received a positive evaluation from EMA in July 2020; it is indicated for the treatment of adult patients with transfusion-dependent anemia due to very low, low and intermediate-risk MDS with ring sideroblasts, who either had an unsatisfactory response to, or are ineligible for, ESAs.

The availability of Luspatercept in different European countries is still not clear, but more information will become available in coming months.


  • Fenaux P, Platzbecker U, et al, List AF. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 2020 Jan 9;382(2):140-151.

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  • Based on a large prospective randomized phase III trial, azacitidine is approved by EMA as first-line treatment for patients with IPSS high and int-2 risk MDS.
  • In these patients, AZA significantly prolongs overall survival compared to treatment with low-dose ara-C and supportive care.
  • The overall CR+PR rate to AZA is 29% and the total rate of CR+PR+HI is 49%.
  • In a smaller sub-cohort of the same study there was no significant benefit of AZA over AML-like chemotherapy, however other retrospective analyses suggest greater efficacy of AZA in patients with poor risk cytogenetics and/or TP53 mutation
  • AZA is less myelosuppressive than chemotherapy, does not cause mucositis, and can be administered at advanced age including patients older than 80, in the absence of major comorbidities
  • AZA is approved in EU in “non proliferative” CMML2, based on a smaller cohort included in AZA 001 trial.
  • Retrospective data in limited patient numbers also consistently show effectiveness of AZA/DAC in advanced CMML (other than “non proliferative” CMML2)
  • Currently no AZA combination strategy has demonstrated a significant survival advantage over AZA monotherapy. Several reports, although mostly in elderly AML, suggest that the addition of Venetoclax to AZA may improve its efficacy. Likewise, but also mainly in elderly AML, the combination of IDH1 or IDH2 inhibitors to AZA appears to improve the outcome over AZA alone, in patients with the respective mutation.

Indication for treatment

  • Approved indications
    • IPSS high or intermediate-2 risk MDS
    • CMML2 with WBC <13 x 109/L
  • Other widespread indications of AZA/HMAs  in higher risk MDS/CMML and MDS-AML
    (based on prospective non randomized or retrospective studies ):
    • Bridging to allo-SCT, especially in patients with unfavourable karyotype
    • Treatment of relapsed disease after allo-SCT (retrospective data suggest AZA ± DLI is feasible and might induce responses and prolong survival)

Predictive factors of response and survival

  • A survival benefit is seen for patients who achieve CR or PR and also for those with stable disease and improvement of cytopenias (IWG criteria )
  • A rapid improvement in platelets (especially after the first cycle) might predict subsequent response and a survival advantage
  • Several studies have evaluated the association between the mutational profile and response. Higher response rate for patients with TET2 or IDH 1/2 mutations have been demonstrated but without effect on survival.
  • Better overall survival has been suggested for patients with mutations in ASXL1/ EZH2 . These associations are however weak and cannot be used to select patients who will benefit from Aza treatment. On the other hand, unfavorable mutations (especially TP53) are also associated with shorter survival
  • No routinely available test assessing the baseline epigenetic status and/or its evolution with AZA/HMAs can reliably predict response or survival with HMAs


general aspects

  • The median number of AZA cycles in the randomized study was 9. Response should not be evaluated before 6 cycles, unless there are signs of progression or in case of planned SCT. Doses should, if possible, not be reduced or cycles delayed during the first 6 cycles, unless severe infection or worsening of major comorbidities.
  • If cytopenias and complications are observed, one may increase interval between cycles or dose reduce for each cycle.
  • For patients with durable response, it is recommended to perform a BM sample annually or in case of worsening cytopenia. Long-term responders may develop cytopenia based on bone marrow hypoplasia over time, and dose reduction may be effective.

Response assessment

  • Responses according to IWG 2006 criteria.
  • IWG CR may be difficult to achieve due to the effect of the subsequent cycle, especially on the neutrophil count.

Azacytidine dosing

  • Retrospective data with limited patient numbers and a prospective trial (but in lower risk MDS, and assessing only response) suggest that a “5-2-2” regimen of AZA ( 75 mg/m2/day for 5 days, followed by 2 days of rest, then 75 mg/m2/day for 2 days) may be equivalent to the recommended 7 day regimen although this remains uncertain. In real life, however, because day care facilities for AZA administration are generally closed on WE, this 5-2-2 regimen is often applied
  • There is no solid scientific evidence for treatment schedule changes in patients with prolonged response

Infectious complications after HMA treatment

  • The rate of  infectious complications with AZA is high, mainly during the first three azacitidine cycles. There are no controlled, prospective studies assessing antibacterial and anti fungal prophylaxis in MDS patients treated with HMA. Anti-infective prophylaxis cannot be recommended in the guidelines.  
  • Likewise, there are no prospective studies assessing the use of G-CSF in neutropenic patients

Management of patients in case of ΑΖΑ resistance/failure

  • Primary or secondary failure of HMAs is associated with a median survival of 5 to 6 months. A recent prognostic system (post-HMA model) based on “classical” factors including age, PS, cytopenias, cytogenetics, and marrow blast % (Nazha  et al), may help segregate patients with somewhat less severe outcome
  • With the exception of allo-SCT, no second-line therapy has demonstrated a survival advantage over best supportive care.
  • Patients should therefore be considered for clinical trials with investigational agents

Recommendation levels

Recommendation for first-line treatment with AZA
  • Recommendation grade A, evidence level I


  • Fenaux, Mufti et al. 2009)
  • Itzykson et al. 2011,
  • Tobiasson et al. 2016,
  • Kuendgen et al. 2018)
  • Alfonso, Montalban-Bravo et al. 2017)
  • Wells, Leber et al. 2014)

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  • Treatment with intensive (AML) chemotherapy (like “3+7”) can be used for cytoreduction in high risk MDS, especially with > 10% bone marrow blasts.
  • There is no evidence that high risk MDS patients with 5-10% bone marrow blasts benefit from cytoreduction prior to start conditioning for an allogeneic hematopoietic cell transplantation
  • Ultimately, intensive chemotherapy should be followed by an allogeneic hematopoietic cell transplantation

Indication for treatment

  • High risk MDS with > 10% bone marrow blasts.

Decision model for treatment with intensive chemo (“3+7”)

  • All ages considered fit for intensive chemotherapy are eligible
  • In individuals with poor risk cytogenetics (e.g. TP53 mutated, -7, etc.), treatment with HMA should be strongly considered instead of intensive chemotherapy

Hematological response

  • Responses are assessed according to AML response criteria as reported in the ELN2017 recommendations.

Treatment with intensive chemotherapy

Important general notes

  • Highly specialised treatment with significant adverse events. Should only be used in departments with experience of this treatment
  • The donor search should be started prior to start chemotherapy (as possible), to allow immediate application of allogeneic hematopoietic cell transplantation in case of persistent aplasia after intensive chemotherapy.
  • Selective gastrointestinal decontamination according to local protocols
  • Anti-fungal prophylaxis according to local protocols.


  • “3+7” as used for the treatment of AML, according to local preference (e.g. daunorubcine 60 mg/m2 for 3 days and cytarabine continuous infusion at 100 or 200 mg/m2 per day for 7 consecutive days.
  • If no response after 1 cycle of intensive chemotherapy, switch to HMAs

Recommendation levels - intensive chemotherapy in MDS

Recommendation intensive chemotherapy for high risk MDS with > 10% bone marrow blasts
  • Recommendation grade A, evidence level 2.


  • The evidence:
    • The number of trials is limited
    • The number of tested patients in each is small
    • The reports are either phase I/II, retrospective, or other types of analysis
    • No phase III RCT, making it difficult, to draw conclusions (evidence level 2)
  • Recommendations:
    • Fit patients (independent of age): “aggressive” with intensive chemotherapy induction regimen, with allogeneic HCT; consider HMA in refractory/relapsing disease
    • Fit patients (independent of age) and poor risk cytogenetics: consider HMAs for cytoreduction instead of intensive chemotherapy
    • Unfit patients: Any reasonable treatment: Supportive; clofarabine can be considered; HMA; Experimental


  • Becker et al, Annals of Hematology, 2015
  • Selleslag et al, Haematologica, 2017
  • Roberts et al, Leukemia Research, 2015
  • Burnett et al, Blood, 2012
  • Ades et al, Haematologica, 2017
  • De Witte et al, Annals of Hematology, 2015
  • Xie at al, PloS On,e 2016
  • Wu et al, Leukemia & Lymphoma, 2015
  • Tinsley et al. 2017, Clinical Lymphoma, Myeloma & Leukemia
  • Malcovati L et al, Blood 2013.
  • Welch, NEJM, 2018

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Stem cell transplantation (SCT)

Stem cell transplantation (SCT)

General factors playing a role to recommend and to time a SCT for patients with MDS

  • Patient characteristics: fitness, performance status, co-morbidity (Sorror ML, et al), wish of the patient and transfusion burden/intensity
  • Disease characteristics, which determine response to chemotherapy and hypomethylating agents: (cyto)genetic characteristics and disease stage at transplantation
  • Disease characteristics, which determine risk of relapse after SCT: (cyto)genetic characteristics and disease stage
  • The availability of a suitable donor: based on current general SCT recommendations
  • The choice of the intensity of the conditioning regimen: based on number and severity of co-morbidities and fitness of patient and molecular characteristics of the MDS. (Lindsley, et al)
  • Response and disease status after given treatment prior to start SCT
  • All fit patients with high-risk MDS according to IPSS-R are candidates for alloSCT, if they have good performance status

Definitions relevant for selecting patients with MDS for allogeneic SCT

  • Non-fit: patients with multiple (> 3) co-morbidities according to HTC-I (Sorror et al)  and/or poor performance (Karnofsky <70)
  • Fit: patients with <3 co-morbidities and good performance status (Karnofsky >60)
  • No upper age limit, if patients are fit, without serious co-morbidity and good Karnofsky status
  • Nontransplant strategies according to most recent versions published by international MDS expert groups, including ELN and NCCN
SVG Flow diagram of High-risk HSCT guidelines - Do not delete this box - can be moved in source view only

Cytoreductive therapy prior to conditioning

  • The expert panel agreed to propose cytoreductive therapy in higher-risk MDS patients with more than 10% marrow blasts
  • Both intensive chemotherapy (ICT)  and hypomethylationg agents (HMA) are accepted interventions; for patients with unfavorable (cyto)genetic abnormalities (mutated TP53, -7, etc.) HMA might be the preferred cytoreductive therapy
  • Patients in CR after 1 or 2 courses of  ICT are candidates for SCT; the role of additional  consolidation courses is unclear. Patients who have failed ICT may be candidates for hypomethylating agents or investigational SCT
  • Patients in CR, PR after 3 to 4 courses of HMA are candidates for SCT 
  • Patients  who have stable disease or who have failed HMA therapy are candidates for investigational SCT.
SVG Flow diagram of Low-intermediate-risk HSCT guidelines - Do not delete this box - can be moved in source view only

Lower-risk MDS recommendations

Failure of nontransplant strategies: ESAs, lenalidomide and cytoreductive therapy, including HMA.  Nontransplant interventions may include more than one line of nontransplant intervention, e.g. treatment with ESAs, followed by lenalidomide in patients with 5q-
Poor risk features:

  • (very) poor risk cytogenetic/molecular characteristics
  • persistent blast increase (>50% increase from base line or with >15% BM blasts)
  • life threatening cytopenias: neutrophil counts < 0.3 x 109/l; platelet counts <30 x 109/l) or drop of platelets >50% during  6 months (Itzykson R, et al)
  • high transfusion intensity >2 units/month for 6 months 
  • molecular testing is generally recommended, especially in case of absence of poor risk cytogenetic characteristics or persistent blast increase

Prevention and treatment of transfusion-related toxicity after SCT in MDS

No accepted method to monitor iron overload in the transplant setting. In practice: ferritin levels are used despite some drawbacks, but LPI levels might be more relevant.

Treatment of iron overload prior to HSCT

No prospective studies, but an expert panel recommended appropriate iron chelation prior to HSCT in MDS patients with a RBC transfusion history of >20 units, who are candidates for HSCT.

Treatment of iron overload after HSCT

The expert panel recommended treatment of iron overload after HSCT in patients with a high transfusion burden. The choice between phlebotomies (if neccessary, supported with epo) and iron chelation remained open due to the lack of prospective studies, but phlebotomies are recommended in patients receiving nephrotoxic drugs (calcineurin inhibitors) . The treatment should start within 6 months after HSCT.


  • Selection of MDS patients for standard and investigational allogeneic stem cell transplantation requires intensive evaluation of patient- and disease-related factors
  • Age is not the major determining selection criterium, if fitness/vitality and co-morbidities (HTC-CI) are evaluated carefully
  • New effective nontransplant treatment modalities may lead to delay or reduction of allogeneic  SCT in MDS in the future.
  • Improved description of genetic features may contribute to the optimization of the pre-transplant strategies and the accuracy of selecting patients for allogeneic SCT. (Welch JS, et al)
  •  This approach may lead to a better outcome after allogeneic HSCT.


  • Sorror ML, et al Blood. 2005;106:2912-9.
  • Welch JS, et al. N Engl J Med 2016;375:2023-36
  • Lindsley, R. C., et al. N Engl J Med (2017); 376(6): 536-547.
  • De Witte T, et al. Blood 2017; 129: 1753-62
  • Itzykson R, et al. Blood Adv. 2018;2:2079-89

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SCT interactive treatment decision tool

Progress through the decision tree by clicking the relevant patient-specific options. Clicking an already selected option, at the left, will take you back to that level in the decision process.

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