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Entries in Myelodysplastic Syndrome (4)

Myelodysplastic Syndrome - Treatment

Even though the IPSS scoring and risk group for the patient can be identified relatively easily, there are still no consensus when it comes to treatment guideline. In other words, when it comes to decision about treatment, the IPSS risk grouping may play just a small role. The more important consideration would be patient’s age and general well-being. As MDS is often a disease of the elderly, not all treatment modalities can be explored. The Haematologist need to assess the state of the patients heart, liver, lungs and kidney before final decision can be made. If the patient has other medical conditions such as diabetes and heart disease, giving too intense a treatment regime may be detrimental to the patient’s health and will not be suitable.

Long-term survival according to risk groupTo simplify matters, the treatment options for MDS can be broadly divided into 4 main groups; 1) supportive, 2) low-intensity, 3) high-intensity and 4) palliative. The low-intensity group proves to be the most controversial and will be discussed last. Supportive care is usually offered in patients in the low risk groups or in elderly patients in the higher risk groups. The idea here is to impart minimal treatment on the patient, and the purpose of the transfusion is not to normalise the patient’s counts, but to increase it enough to a level where the patient will not have symptoms. The emphasis here is to increase the quality of life while minimising potential harm.

Summary of the treatment optionsIn the very elderly, or advanced risk group, it may be appropriate just to palliate the patient. The idea here stems from the understanding that intensive therapy will be futile or will even hasten the patient’s demise. It may also impart unnecessary cost and suffering to the patient. The patient will be given transfusion if needed, and treated for infection if this becomes an issue. Palliation does not mean leaving the patient to die without any intervention. Most tertiary hospitals now have Specialist Palliative Care Physician who will help the patients and family through this trying time. Palliative care will be discussed in another entry.

In the young patient, where long-term cure is a reasonable target, the patient may be a candidate for bone marrow transplant. There is controversy however in terms of timing. Most centers, including ours believe that transplant should be offered early in suitable candidates where complications of transfusion and infection has not yet set in. It is imperative not to wait until transformation occurs as success rate from transplantation at this stage of MDS is very poor. Once transformation occur, chemotherapy similar to patients with acute leukaemia will be needed to take the patient into the remission phase. However, this remission phase is often hard to achieve and even if so will be short-lived. The patient then will need to be transplanted as soon as possible. Data also suggest that the relapse rate in MDS patients undergoing transplant especially once where transformation has occurred is much higher if compared to AML patients or in patients with MDS where transformation have not yet occurred. The take home message here is, bone marrow transplant offers the only possibility of long-term remission and is best to be done early in the disease course.

Low-intensity therapy form the grey area in MDS treatment. Here, a combination of patients’ age and unsuitability for bone marrow transplant put the chance of long-term disease control slim, but in the meantime, the patient may be fit enough for more than just supportive care. The options are broad and there is no right answer for everybody. Often the treatment offered will depend on patient’s preferences and the Haematologist’s experience in using the available drugs. Some of the drugs have horrendous side-effect while others, are very expensive - azacytidine, lenalidominde and decitabine to name a few. It is often sensible to start with growth factors, such as erythropoeitin and G-CSF, either separately or in combination. The next option would be immunosuppression. Steroids, danazol, cyclosporine, thalidomide and mycophenolate have been tried with various level of success. This may be especially appropriate in subgroup of patient where marrow aplasia - empty marrow - is prominent. In a special subgroup - the 5q- syndrome - thalidomide and lenalidomide have been proven to be very effective.

In the last few years, a new group of novel agents have emerged from clinical trials. These are the HDAC inhibitors and the hypomethylating agents. The two hypomethylating agents currently available in the market are decitabine and azacytidine. Both has been proven to prolong the patients live by a factor of a few months. It is not clear however if they both can prevent the progression of the disease into leukaemia. Our center has so far only been able to use decitabine. The main issue being the cost to the patient. Suffice to say it is prohibitive, and there will also be risk of complications that will incur further cost to the patient later on. However, these novel agent will be the option for the future and I am sure over time, the cost will become reasonable.

There are also patients who may benefit from low-dose chemotherapy to help stem down the population of blast cells in circulation. However, they do not prevent progression of disease or delay transformation into leukaemia. Its use should be weight against the risk of infection and organ damage.

All in all, decision about treating patients with MDS is never clear cut. Extensive discussions with the patients and relatives are very important.

Myelodysplastic Syndrome - Classification and Prognostication

Simple prognostic figures by the FAB classificationBefore treatment options can be discussed, it is very important to talk to the patients at length about what the diagnosis mean to them. In a nutshell, MDS carries a long-term risk of terminal transformation into acute leukaemia, which will be resistant to chemotherapy and even bone marrow transplant. Currently, conventional treatment has minimal bearing in terms of delaying the inevitability. Treatment may also give serious side-effect which in itself may shorten the patients’ survival. The important thing here is to maximise the quality of life in patients where the prognosis is poor. The only chance for long-term cure would be with bone marrow transplant which should be offered to suitable candidates. Once patient is identified into these prognostic group, the prognosis then becomes clearer, and it will be easier to plan long-term treatment.

This chapter will concentrate just on the prognostication process, and I will leave the treatment in a later entry.

Ever since the days of the FAB classifications for MDS, it has become very clear that the different subgroup has different outcome. Looking at historical data, an attempt was made at putting figures into this fact, as highlighted in the chart up top. This may suggest that the further down the list we go, the more advance the disease is, but in real life, that may not be the case. We have seen patient with CMML living longer than RAEB. This figures just serve as a simple guide.

With the introduction of the WHO classification, further calculations were made to look at median survival - the time it takes for 50% of patients to pass away from time of diagnosis - and the rate of transformation into acute leukaemia. The IPSS (International Prognosis Scoring System) classify the outcome in patients with MDS based on 4 factors - the first 3; the amount of blast percentage in the bone marrow, cytogenetics studies (study of chromosome in stem cells) and the number of lineage of blood cells affected; was scored to give the 4 risk groups - low, intermediate-1, intermediate-2 and high. The risk group was then tabulated against a fourth factor, age, to determine the median survival and risk of transformation.

A score was determine from looking at the above 3 factors, bone marrow blast percentage, karyotypes and cytopenias.The number was then used to assign the patient into the appropriate risk groupsThe IPSS is useful in a couple of senses, the risk group can form the base for discussion of treatment options, and the score can also be used for calculation of overall survival.

The outcome risk as tabulated with patients age in terms of survival in yearsOnce the patient risk group was identified, a more in depth discussion about treatment can be made. Again, I can not emphasise more the importance of bone marrow assessment in patients with MDS. One can only obtain cytogenetics study from the marrow, as well as the need to calculate the percentage of marrow blast cell to come up with the IPSS score. There are also alternative scoring system such as the WPSS, which is beyond the scope for this site.

Myelodysplastic Syndrome - Diagnosis and Presentation

As the diagram indicate above, and from more reasons I will elaborate later, examination of bone marrow is a must in diagnosing this condition. There will be obvious discrepancy between what is seen in the bone marrow and peripheral blood, highlighting the point about abnormal maturation of the cells in the marrow which were ultimately not released into the circulation due to their defect. This also explains the main way the disease present, lack of blood cells in circulation, anaemia.

Anaemia in the elderly can appear as lethargy, low energy level, dizzy spells and palpitations. If the patient has underlying heart disease, they may experience chest pain and angina attacks, breathlessness due to heart failure, ankle oedema and if severe, even heart attack. In rare instances, patients may appear with autoimmune phenomenon, haemolysis, jaundice and enlarged spleen.

When it comes to blood tests, the patient may also develop low platelet count, and appearance of abnormal protein in circulation - paraproteinaemia. Under the microscope, the circulating red blood cells also appear abnormal - they may have abnormal markings and shapes. They may also have primitive cells in the peripheral blood, similar to patients with leukaemia - the so-called blast cells. These appearance may alert the Haematologist to investigate the patient further.

Other condition that may mimic MDS during presentation include aplastic anaemia, megaloblastic anaemia due to lack of vitamin B12, atypical CML and myelofibrosis.

During diagnosis, it is important to establish the subgroup of the disease the patient belongs to. Similar to patient with cancer, the first step of investigation is called staging. In MDS, conventional staging with CT scans in lymphoma and other solid organ cancer do not apply. Instead, to stratify patient into prognostic groups, we device some clever markers in the tests that patient go through during staging. This brings the discussion into MDS disgnosis and prognosis subgroups, two almost separate discussion. I will cover the diagnostic subgroup in this entry and leave the prognostic group for later. Why are these subgrouping important? By doing so, treatment plan will be easier. We can later lump the patient into treatment algorithm to give the best outcome depending on the subgroup the patient belongs. The subsequent prognostic discussion will also stem from these initial staging tests. We can then predict the probable outcome in the patient in terms of survival and chances of the disease turning into leukaemia.

The FAB ClassificationThe first idea for staging or classifying MDS came in 1982 with the introduction of the FAB (French-American-British) Classification. They proposed segregation into 5 distinct groups, depending on the percentage of blast in 1) bone marrow and 2) peripheral blood, 3) presence of Auer rods - a special marking inside the blast cells, 4) presence of monocyte in blood - a form of white blood cell, and 5) presence of special stain on the red blood cells - ring sideroblast. The subgroup is best illustrated by the chart below.

The FAB classification was soon realised to not reflect treatment outcomes as well as expected, and the WHO working group then proposed modification to the original FAB system. It looked  specifically at the clinical presentation in the patients, amount of bone marrow blast cells and cytogenetics of the patient.

The WHO ClassificationOnce the patient’s disease subgroup is identified, the treatment plan can then be discussed. This will be highlighted in the next entry.

Myelodysplastic Syndrome - Introduction

Myelodysplastic syndrome or MDS is not a common diagnosis. In most patient, the diagnosis came out of the blue, as part of investigations for abnormal blood test. The abnormal blood test were often anaemia, without much symptoms in the patient. There was typically no period of illness. There was no organ swelling to alert the patient of the diagnosis. Quite often the diagnosis came later in its course, in the form of acute leukaemia.

As the name suggest, MDS is a condition where by the stem cell and its early progenitor which were supposed to produce daughter cells in the form of mature red and white blood cells and platelet, became defective or dysplastic. These abnormal or dysplatic cells, do not produce viable cells to go in circulation, and often our body’s own mechanism will prevent its release. They are stuck in the patient’s marrow. Consequently, the patient will have low peripheral blood count but when a bone marrow aspirate tests were performed, there will often be very cellular. This is the hallmark of MDS. This abnormal cell will accumulate over time and the mutation can result in transformation into leukaemia, the most feared outcome of this condition.

The job of the Haematologist is first to diagnose the condition. Once this is established, tests will be done to see in which prognostic group patient belong. From here, we can predict how likely the disease will transform into leukaemia, and when and what form of treatment suits the patient best. Therefore, treatment for this disease is very individualised and best handled by at a specialised center. 

The disease usually presents in the elderly population with a slight male preponderance just as with other cancers, often as incidental finding. There is a subgroup of patient who develop MDS due to previous chemotherapy treatment for haematological or other cancer. This subgroup has a worst prognosis and often transform into leukaemia very quickly. Apart from that, MDS is not an inherited condition, nor due to previous infection. To discuss this condition, I will divide my entries into; diagnosis and classification, prognostic markers established, and available treatment options.