Myelodysplastic Syndrome

from Wikipedia, the free encyclopedia
Classification according to ICD-10
D46 Myelodysplastic Syndromes
D46.0 Refractory anemia without ring sideroblasts
D46.1 Refractory anemia with ring sideroblasts
D46.2 Refractory anemia with excess blasts [RAEB] RAEB I

RAEB II

D46.4 Refractory anemia, unspecified
D46.5 Refractory anemia with multiline dysplasia
D46.6 Myelodysplastic syndrome with isolated del (5q) chromosomal anomaly

5q minus syndrome

D46.7 Other myelodysplastic syndromes
D46.9 Myelodysplastic syndrome, unspecified; Myelodysplasia onA; Preleukemia (syndrome) onA
ICD-10 online (WHO version 2019)
Classification according to ICD-O-3
9980/3 Refractory anemia Refractory anemia without sideroblasts
9982/3 Refractory anemia with sideroblasts RARS Refractory anemia with ring sideroblasts Refractory anemia with ring sideroblasts associated with pronounced thrombocytosis
9983/3 Refractory anemia with excess blasts RAEB RAEB I RAEB II
9984/3 Refractory anemia with excess blasts in transformation [obs.] RAEB-T
9985/3 Refractory cytopenia with multiline dysplasia Refractory cytopenia in childhood
9986/3 Myelodysplastic syndrome with 5q deletion (5q-) Myelodysplastic syndrome with isolated del (5q)
9987/3 Therapy-related myelodysplastic syndrome onA Therapy-related myelodysplastic syndrome due to alkylants Therapy-related myelodysplastic syndrome due to epipodophyllotoxin
9989/3 Myelodysplastic Syndrome NOS Myelodysplastic Syndrome, not classifiable Preleukemia [obs.] Preleukemic syndrome [obs.]
9991/3 Refractory neutropenia
9992/3 Refractory thrombocytopenia
ICD-O-3 first revision online

The term myelodysplastic syndrome ( MDS , myelodysplasia or plural myelodysplastic syndromes ) covers a group of diseases of the bone marrow in which blood formation does not originate from healthy but from genetically modified cells of origin ( stem cells ). The bone marrow of patients with myelodysplastic syndromes is no longer able to produce fully mature and functional blood cells from these stem cells .

In the advanced stages of these diseases, more and more immature blood cells are produced. The blood formation process is therefore permanently disturbed and can also lead to acute myeloid leukemia (AML) in some patients at a later point in time .

The myelodysplastic syndromes mainly occur at an advanced age - from around 60 years - and develop very differently from patient to patient. The median age of onset is around 75 years, women are affected somewhat less often than men. The treatment options have improved significantly in the last few years, but are very differentiated in view of the complex development of the disease and take into account the distinction between low-risk and high-risk MDS.

Research programs to combat this disease are running at several universities, for example at Heinrich Heine University in Düsseldorf . The MDS register Düsseldorf aims to characterize the disease biologically as well as possible, to predict the course of the disease as well as possible and to determine the most suitable therapies for the patient. The initiative, which started in 2003, expands the activities by cooperating with numerous clinics working in the field of MDS ( Göttingen , Duisburg, Dresden, Mannheim, Ulm, Munich r. D. I. and Cologne).

Blood cells colored

Course of disease

The patients gradually lose more and more strength. The Hb value and the hematocrit , i.e. the measured value that mainly depends on the concentration of erythrocytes and the distribution of solid and liquid components, decrease dramatically. One tries to stop this either by blood transfusions, usually weekly or fortnightly, or by injections of erythropoietin once a week . At the same time, the number of thrombocytes, which are partly responsible for blood clotting, and the number of white blood cells ( leukocytes ) responsible for the immune system also decrease significantly. This is why MDS patients suffer more and more from sudden bleeding in the gums , in the nose and particularly dangerous in the stomach and intestines as the disease progresses . As the disease progresses, hematomas develop all over the body, from face to feet . Furthermore, those affected are extremely susceptible to infections of all kinds and must absolutely avoid crowds. Most MDS patients die of internal bleeding or pneumonia because this no longer responds to strong antibiotics .

In about 30% of all MDS cases, the disease suddenly turns into acute leukemia after a certain period of time , which many patients do not survive long because of their weakened condition, even with chemotherapy initiated immediately .

Division / classification

The myelodysplastic syndromes are classified according to the appearance of the blood cells. A distinction is made between five types according to the type and proportion of immature blood cells in the blood itself and in the bone marrow.

Two classification systems are currently competing for the classification of myelodysplastic syndromes: the FAB classification and the WHO classification. The current form of the FAB classification was brought into being in 1982 by an international working group.

FAB classification of myelodysplastic syndromes

FAB classification of myelodysplastic syndromes
FAB subtype Properties of the bone marrow Properties of blood annotation ICD-10 coding
RA (refractory anemia ) <5% blasts ≤ 1% blasts Early stage of MDS. The proportion of immature cells, so-called blasts , is not increased in the bone marrow and is less than 5% of all nucleated cells. D46.0
RARS (refractory anemia with ring sideroblasts ) <5% blasts
> 15% ring sideroblasts
≥1% blasts D46.1
RAEB (refractory anemia with excess blasts) 5-20% blasts <5% blasts RA with proliferation of blasts (5–20% myeloid differentiated blasts). Divided into RAEB-1 (5–9% blasts) and RAEB-2 (10–19% blasts). D46.2

(Incl .: RAEB I and RAEB II)

CMML ( chronic myelomonocytic leukemia ) <20% blasts
increased promonocytes
> 1 × 10 9 / l monocytes
<5% blasts
C93.1-

(Incl.

  • CMML-1
  • CMML-2
  • CMML with eosinophilia
  • C93.10 CMML: Without specification of a complete remission
  • C93.11 CMML: in complete remission)
RAEB-T (RAEB in transformation) 21–30% blasts of
Auer rods
> 5% blasts Precursor to acute myeloid leukemia .

D46.4 Refractory anemia, unspecified

WHO classification

Schematic illustration of the bone marrow architecture

In 1999 the FAB classification - with the cooperation of some members of this FAB working group - was expanded into the so-called WHO classification. The latter separates more precisely from a prognostic point of view, but is also significantly more complex. The second currently valid version of the WHO classification was published in 2009 and contains minor changes to the 1999 version.

WHO classification (2016) of myelodysplastic syndromes
category Dysplastic series Cytopenias Ring sideroblasts (% of erythroid cells) Blasts in the bone marrow (BM) and peripheral blood (PB) Karyotype (conventional banding)
MDS with single-line dyslasia 1 1 or 2 <15% / <5% BM <5%, PB <1%,

no Auer chopsticks

All except del (5q) +/- 1 other non-Chr. 7 aberration
MDS with multiline dysplasia 2 or 3 1 to 3 <15% / <5% BM <5%, PB <1%,

no Auer chopsticks

All except del (5q) +/- 1 other non-Chr. 7 aberration
MDS with ring sideroblasts
MDS with ring sideroblasts and single-line dysplasia 1 1 or 2 ≥15% / ≥5% BM <5%, PB <1%,

no Auer chopsticks

All except del (5q) +/- 1 other non-Chr. 7 aberration 5q
MDS with ring sideroblasts and multiline dysplasia 2 or 3 1 to 3 ≥15% / ≥5% BM <5%, PB <1%,

no Auer chopsticks

All except del (5q) +/- 1 other non-Chr. 7 aberration
MDS with del (5q) 1 to 3 1 to 3 irrelevant BM <5%, PB <1%,

no Auer chopsticks

del (5q) isolated or with 1 other non-Chr. 7 aberration
MDS with excess blasts
MDS with excess blasts (1) 0 to 3 1 to 3 irrelevant BM 5–9% or PB 2–4%,

no Auer chopsticks

irrelevant
MDS with excess blasts (2) 0 to 3 1 to 3 irrelevant BM 10–19% or PB 5–19%,

or Auer chopsticks

irrelevant
MDS, unclassifiable
with 1% peripheral blasts 1 to 3 1 to 3 irrelevant BM <5%, PB = 1%,

no Auer chopsticks

irrelevant
With single-line dysplassia and pancytopenia 1 3 irrelevant BM <5%, PB <1%,

no Auer chopsticks

All except del (5q) +/- 1 other non-Chr. 7 aberration
Based on defining cytogenetic changes 0 1 to 3 <15% BM <5%, PB <1%,

no Auer chopsticks

MDS-defining abnormality

IPSS & WPSS risk assessment

Forecast estimation

The risk assessment for MDS is carried out using so-called forecasting systems or scoring systems. In general, all prognostic systems for blood diseases work according to the same pattern: Certain individual factors are weighted and combined in order to estimate the life span of the patient without treatment. In MDS disease, different prognostic scores combine different individual factors in order to calculate the median survival time without treatment. The aim of the therapy is to extend the statistically expected lifespan.

International forecast score for MDS

The most widely used prognosis score for MDS is the IPSS score. IPSS stands for International Prognostic Scoring System. This classification combines three factors: How severe is the lack of blood cells (so-called cytopenias)? How badly is the genetic make-up of the cells responsible for blood formation changed (so-called cytogenetic changes)? How high is the proportion of immature cells in the bone marrow that are indicative of an imminent transition to leukemia (so-called bone marrow blast proportion)?

WHO-adapted prognosis score for MDS

The WPSS (WHO adapted prognostic scoring system) calculates life expectancy in a similar way: Here too, the proportion of blasts in the bone marrow and cytogenetics are included . Instead of the cytopenias, however, the WPSS uses the information as to whether a patient has previously had to receive red blood cells or not.

Prediction of survival time by risk group

Risk group score mitt. Survival time in years AML 25%
attractively priced very low <1.5 8.8 not reached
Cheap low > 1.5-3 5.5 10.8
intermediate intermediate > 3-4.5 3.0 3.2
unfavorable high > 4.5-6 1.6 1.4
very inconvenient very high > 6 0.8 0.73

therapy

Basically, therapeutic measures are carried out according to the risk assessment of the MDS disease. So-called scoring systems are used for risk assessment. The most common scoring system currently used is the International Prognostic Scoring System (IPSS). The risk groups low and intermediate-1 are classified as low-risk MDS, while the intermediate-2 and high-risk populations are classified as high-risk patients.

Low-risk MDS

  • Supportive therapy (= supportive treatment, i.e. treatments that treat complications of the disease without influencing the natural course of the disease):
    • It includes the administration of red blood cells ( erythrocytes ) or blood platelets ( thrombocytes ) when these blood values ​​are low and antibiotics for infections.
    • When patients have low white blood cell counts ( leukopenia , neutropenia, or granulocytopenia ), certain growth factors may increase the number of white blood cells in the blood. These substances are called granulocyte colony stimulating factors ( G-CSF ).
    • Patients in need of transfusions run the risk of developing severe iron overload as their disease progresses . This is due to the fact that the red blood cells contain hemoglobin , which binds oxygen and transports it to the tissues. Hemoglobin contains iron. With every bag of erythrocytes (red blood) that a patient receives, they automatically ingest an amount of around 200–250 mg iron. That's a lot compared to a natural daily iron intake of around 1 mg per day. Excretion in humans is also limited to 1 mg, so that blood transfers inevitably lead to an increase in body iron. While healthy people contain around 3–4 g (i.e. 3000–4000 mg) of body iron, this amount can easily increase tenfold in patients requiring long-term transfusion. In these amounts, however, iron is harmful because it is deposited in liver tissue, heart and glandular tissues and leads to disorders there. In order to be able to excrete iron, so-called iron chelators are now available, which can lower the body iron level if taken regularly.
    • In addition, care should be taken not to give patients with low platelet levels any medication that further inhibits the function of the few remaining platelets, such as so-called non-steroidal anti-inflammatory drugs ( acetylsalicylic acid (aspirin), diclofenac , ibuprofen , naproxen and others). This can lead to life-threatening bleeding. In some patients, the platelet counts do not go up even though they are given platelets. These patients are called refractory to platelet transfusions. The cause is usually the formation of antibodies after frequent transfusion treatment. In these cases, antifibrinolytics such as para- aminomethylbenzoic acid can be used to reduce the tendency to bleed.
    • Several international studies have shown that erythropoietic growth factors ( erythropoietins or EPO, i.e. drugs that increase the number of red blood cells) can, under certain conditions, lead to a temporary but lasting increase in hemoglobin levels. A recently published index predicts the likelihood of response to erythropoietin therapy. This index combines the number of transfusions performed with the current erythropoietin level. Patients who need many transfusions and who have high EPO levels are less likely to respond to the drug.
  • Immunosuppressive measures are based on the knowledge that (autoreactive) cytotoxic (cell-damaging) T cells (a subtype of lymphocytes) directed against one's own body are involved in the development of insufficient blood formation via inhibitory messenger substances ( cytokines ).
    • In a phase II study at the National Institutes of Health in the USA, 61 patients with RA, RARS or RAEB with anemia requiring transfusion or thrombocytopenia were treated with the substances antithymocyte globulin and cyclosporine A. 33% of the patients lost their anemia requiring transfusion, 44% showed an improvement in peripheral granulocyte counts and 56% achieved a clinically relevant increase in platelets.
  • Immunomodulating substances whose mode of action, in addition to inhibiting TNF-alpha, also activates T and NK cells and direct pro-apoptotic mechanisms.
    • In addition to inhibiting neovascularization, the substance thalidomide also has cytokine-inhibiting effects and has been successfully used in myelodysplastic syndromes. Early MDS subtypes seem to respond better (40%) than advanced MDS. However, treatment has to be discontinued in up to 30% of patients because of intolerable side effects (fatigue, nerve damage, constipation).
    • In the meantime, thalidomide analogs have been developed that were used in early forms of MDS. The 4-amino-glutarimide lenalidomide has a completely different side effect profile and does not lead to polyneuropathy (nerve damage) or fatigue. The teratogenic effects, however, can still be demonstrated in animal experiments. It is particularly effective in patients with defects on chromosome 5 (so-called 5q MDS): An evaluation of an international phase II study showed that almost 70% of the patients treated were transfusion-free for a longer period of time. About 50% of the patients were still transfusion-free after 2 years of continuous use. 70% of the patients achieved a cytogenetic response (at least 50% reduction in the amount of del (5q) in the bone marrow), 44% a complete cytogenetic response, i.e. H. the typical del (5q) chromosome was no longer detectable. In 2013 the European Medicines Agency approved the drug for patients with isolated del (5q) chromosomal abnormalities.

High risk MDS

  • 5- azacytidine and 5-aza-2'- deoxycytidine ( decitabine ) are pyrimidine analogues which, in non-cytotoxic concentrations, lead to an inhibition of DNA methyltransferase (demethylating substances) and experimentally cause certain bone marrow cells to mature. 5-Azacytidine was approved for the treatment of MDS in the USA after a phase III study showed a survival advantage for treated patients over patients in the control group. According to the most recent evaluation, the rate of complete remissions and partial remissions in the treatment group was 15.7%; the time to transition to leukemia and survival were statistically significantly increased under therapy. The evaluation of an international phase III study in which 5-azacytidine was compared to other therapeutic methods showed a survival advantage for azacytidine. Patients in the azacytidine treatment group survived an average of 24 months, while the mean survival in the control arm was 15 months. Based on these data, the substance was approved on December 23, 2008 for the treatment of advanced myelodysplastic syndromes in Europe.
  • Intensive polychemotherapy with protocols such as those used in AML ( acute myeloid leukemia ) can be used to induce remission in patients <70 years of age. In more recent studies that included at least 30 patients, the full remission rates were 45–79%. The early death rate was similar to that of patients with acute myeloid leukemia. Favorable long-term courses have been documented especially in RAEB / T patients with a normal karyotype. The allogeneic blood stem cell transplantation is the treatment of choice for patients <50 years old with high-risk MDS that have a matching donor. According to data from the Fred Hutchinson Cancer Research Center in the US on a total of 251 MDS patients, disease-free survival six years after transplant is 40%. Age at transplantation is one of the greatest risk factors. Improvements are expected in the next few years through new conditioning protocols such as non-myeloablative transplantation.
  • Chemotherapy may also be supported with all-trans retinoic acid (ATRA). The evidence is very uncertain about the effect of ATRA in addition to chemotherapy on degree third / fourth diarrhea, degree third / fourth nausea / vomiting, and degree third / fourth cardiac toxicity. ATRA added to chemotherapy is likely to result in little or no change in mortality within 24 months, mortality during the study, and grade 3/4 infections. In addition, ATRA, in addition to chemotherapy, is likely to cause very little or no reduction in mortality, relapses, and disease progression.
  • Chemotherapy and stem cell transplants have some side effects. Among other things, both can lead to bleeding events and a stem cell transplant can also lead to a transplant-versus-host reaction. Estcourt et al. In 2012 and 2015, Cochrane reviewed randomized controlled trials to find out which use of platelet transfusions is most effective for preventing bleeding in patients with haematological disorders when receiving chemotherapy or a stem cell transplant. Depending on the use, there were various effects such. B. the number of days with a bleeding event.

Supportive therapy

The treatment of haematological diseases can be supported by increasing wellbeing. Exercise could be one way of doing this, among other things. The evidence is very uncertain about the effect of exercise on anxiety and major adverse events. Exercise may cause little or no change in mortality, quality of life, and physical function. Exercise may cause a small reduction in depression.

literature

Web links

Individual evidence

  1. C. Aul, A. Giagounidis, U. Germing: Myelodysplastic syndromes . In: Internist (Berl). Volume 51, No. 2, February 2010, pp. 169-182.
  2. Myelodysplastic Syndromes (MDS). Retrieved July 11, 2020 .
  3. MDS register Düsseldorf .
  4. University Medical Center Göttingen: Myelodysplastic Syndrome (MDS). October 29, 2019, accessed July 11, 2020 .
  5. MDS register Düsseldorf .
  6. JM Bennett, D. Catovsky, MT Daniel, G. Flandrin, DA Galton, HR Gralnick, C. Sultan: Proposals for the classification of the myelodysplastic syndromes. In: Br J Haematol. Volume 51, No. 2, June 1982, pp. 189-199.
  7. MDS register - valid WHO classification ( Memento of the original from September 24, 2010 in the Internet Archive ) Info: The @1@ 2Template: Webachiv / IABot / www.mds-register.de archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. .
  8. P. Greenberg et al .: International scoring system for evaluating prognosis in myelodysplastic syndromes. In: Blood . Volume 89, No. 6, March 1997, pp. 2079-2088.
  9. a b MDS register - IPSS and WPSS computers .
  10. Myelodysplastic Syndromes. Deutscher Ärzteverlag GmbH, editorial office of Deutsches Ärzteblatt, November 15, 2013, accessed on November 30, 2019 .
  11. Immunomodulatory substances , from the website of the DGHO (onkopedia), accessed on March 12, 2014.
  12. European public assessment report (EPAR) for Revlimid - lenalidomid (e) , in English from the website of the European Health Authority (EMA), accessed on February 14, 2014.
  13. Summary of the EPAR for the public , in German from the website of the European Health Authority (EMA), accessed on February 14, 2014.
  14. Yasemin Küley-Bagheri, Karl-Anton Kreuzer, Ina Monsef, Michael Lübbert, Nicole Skoetz: Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia ( non-APL)) . In: Cochrane Database of Systematic Reviews . August 6, 2018, doi : 10.1002 / 14651858.CD011960.pub2 ( wiley.com [accessed July 9, 2020]).
  15. Sheila A Fisher, Antony Cutler, Carolyn Doree, Susan J Brunskill, Simon J Stanworth: Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition . In: Cochrane Database of Systematic Reviews . January 30, 2019, doi : 10.1002 / 14651858.CD009768.pub2 ( wiley.com [accessed July 9, 2020]).
  16. Lise Estcourt, Simon Stan Worth, Carolyn Doree, Sally Hopewell, Michael F Murphy: Prophylactic platelet transfusion for prevention of bleeding in patients with Haematological disorders after chemotherapy and stem cell transplantation . In: Cochrane Database of Systematic Reviews . May 16, 2012, doi : 10.1002 / 14651858.CD004269.pub3 ( wiley.com [accessed July 9, 2020]).
  17. Lise J Estcourt, Simon J Stanworth, Carolyn Doree, Sally Hopewell, Marialena Trivella: Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation . In: Cochrane Database of Systematic Reviews . November 18, 2015, doi : 10.1002 / 14651858.CD010983.pub2 ( wiley.com [accessed July 9, 2020]).
  18. Linus Knips, Nils Bergenthal, Fiona Streckmann, Ina Monsef, Thomas Elter: Aerobic physical exercise for adult patients with haematological malignancies . In: Cochrane Database of Systematic Reviews . January 31, 2019, doi : 10.1002 / 14651858.CD009075.pub3 ( wiley.com [accessed July 9, 2020]).
  19. Myelodysplastic Syndromes (MDS). Retrieved May 1, 2020 .