Death knell no more, Chronic Myeloid Leukaemia is turning from a fatal to a manageable disease, with patients surviving for years, thanks to medical advancements.
Chronic Myeloid Leukaemia (CML), a type of cancer that affects blood and bone marrow, was incurable until the 1980s. Today, however, that isn’t the case. Advanced studies and research have helped in developing medicines to treat the disease and control it before it reaches a critical stage.
On the eve of World Chronic Myeloid Leukaemia Day, observed on September 22, DNA spoke to Dr Mukesh Desai of Bai Jerbai Wadia Hospital for Children; Dr Bhausaheb Bagal of Tata Memorial Hospital; Dr Tulika Seth from AIIMS; and Dr Dinesh Bhurani from the Rajiv Gandhi Cancer Institute and Research Centre, to talk about CML in India, the work done to treat patients so far and what the future holds.
The discussion, moderated by Sohini Das Gupta, throws light on several aspects of the disease that most people are unaware of. Edited excerpts:
Dr Mukesh Desai (Mumbai)
1) To break it down to the average non-medical person – what is CML?
CML is Chronic Myelogenous Leukaemia, a malignancy of Hemopoietic stem cell and has several phases — Chronic, Accelerated, and Blast Crisis.
2) What causes CML and what are some common symptoms?
A Genetic change in the HSC (Hemopoietic Stem Cell) t(9,22) also called Philadelphia chromosome results in formation of a new gene in which a part of ABL and BCR gene join with each other to form the BCR-ABL gene. The product of this gene directs the HSC towards oncogenesis.
The common symptoms of CML are:
CML commonly affects people in the 3rd and 4th decade of life in India
Presentation is very often with low grade fever, wt loss, mild anaemia and fullness of abdomen after meals due to presence of a large spleen. Some times it may be accidentally discovered due to high WBC count detected on medical check up; Detection of splenomegaly.
3) What age group / sex , which demographic is most susceptible to CML?
In India CML occurs a decade earlier compared to west; Both sexes are affected with a slight male predominance;
4) Are there any lifestyle factors that increase the risk of developing CML?
5) How is CML diagnosed?
CML can be diagnosed by CBC; which show mild anaemia with Hb in range of 8 to 10 gm; a high WBC count with Shift to left and premature cells like Myelocytes and Metamyelocytes being the predominant cells; Basophils are increased; Platelets are normal or increased.
Bone Marrow Aspiration and Biopsy is necessary along with BM Cytogenetics to confirm the diagnosis.
BM will also confirm whether patient is in chronic phase or crisis. Also detection of the Ph chromosome is a must to diagnose CML.
6) What are the different stages of CML?
CML has 3 phases;
1. Chronic phase majority present in chronic phase; in which the patient looks well and can live like a normal person and has an excellent quality of life. in fact if we can maintain patient in Chronic phase he will have no risk to life and an excellent quality of life.
2. Accelerated phase when the disease becomes a little more aggressive, patient may develop more severe anaemia and may require Blood Tx, platelets may increase and over all patient feels more sick.
3. Blast Crisis; in this phase a relatively benign disorder now becomes aggressive and converts itself in to Acute Leukaemia and it is universally fatal
7) Can you give us an optimistic peek into living with CML?
Today advances in Medicine and understanding the biology and aetiology of CML has provided newer treatment options like tyrosine kinase inhibitors (TKI) which has improved the survival of CML and one can say with appropriate treatment and monitoring the survival of patient with CML is as good as that of normal population
8) What about remission? How long does one have to stay vigilant after recovery?
With newer TKI we can achieve not only a Hematological remission but also Cytogenetic remission and a deep Molecular remission. We have reached a stage when we are able to consider stopping TKI under specific condition and as a part of clinical trial and achieve a Treatment Free Remission in almost 40 to 50% of patients of CML and hopefully these patients are cured of their disease. We are awaiting answers from clinical trials and longer follow uo of these patients before they become standard recommendations and we can say that CML is a curable disease.
Dr Bhausaheb Bagal (Mumbai)
CML is a condition when our bone marrow, where normal blood cells are produced start producing very high number of abnormal blood cells.
This happen because of a specific defect in gene of cell, called as philadelphia chromosome. Philadelphia chromosome is a specific genetic abnormality where genetic material between chromosome 9 and chromosome 22 is exchanged and this lead to abnormal and short chromosome 22 having a abnormal portion called BCR-ABL1. This is called as 9;22 translocation which is used for diagnosis and also same reason we observe 22nd September as CML day.
Sometime the person may be completely asymptomatic and CML is diagnosed as one does blood test for some other purpose.
Common symptoms in other patients are –
Weakness, fatigue, left upper abdominal pain because of enlarged spleen.
Done by blood tests and bone marrow examination. Special test like demonstration of BCR-ABL gene clinches the diagnosis.
It has three stages –
Chronic phase- Initial stage, where it can be easily treated with oral medicines called TKI (Imatinib, nilotinib or Dasatinib)
Accelerated and Blast phase –
Are advanced phase with require aggressive management, sometime bone marrow transplant for cure.
Living with CML –
Treatment is very different from other cancer. Its in fact one of the first disease treated with targeted therapy. Since this therapy is unlike other cytotoxic chemotherapy, side effects tend to be mild if at all and can be managed easily.
With advent of TKI, this has become just another manageable disease like diabetics and blood pressure. Most of early stage patients responding to TKI will be able to live normal life and their life span will be similar to healthy individuals.
The disease is so well controlled with TKI that patients can continue their routine jobs/chores.
Since the treatment is oral and lifelong, people tend to misunderstand the importance of close follow up and compliance. Its vital to the success of treatment that we monitor such patients closely with very sensitive tests such as PCR (polymerase chain reaction), so that we detect any sub-optimal response long before it shows up in routine blood tests and patient develop symptom.
Whats new –
Treatment free remission –
In very select subset of patients under clinical trials, patients whose disease is very well controlled for long, these patients have been carefully evaluated for therapy discontinuation attempts. This has to be done very carefully. Discuss with your doctor about TFR. Therapy compliance is utmost important and patients should not stop/omit therapy without doctors advice.
Financial help –
Given the very good prognosis needy patients are usually assisted by many NGO/Government organizations in case they need help with treatment. Speak to your doctor about same.
Dr Tulika Seth & Dr Dinesh Bhurani (Delhi)
…mutation that occurs in the normal Chromosome 9 and 22, and this leads to an increase of proliferation of the white blood cells.
Sohini Das Gupta: Okay. Okay. So it’s essentially an – a spot in the number of white blood cells in the human body?
Tulika Seth: Right. And it’s due to a mild mutation. Many mutations can be genetic. This is a acquired mutation. So it’s not a mutation you’re born with…
Sohini Das Gupta: Okay…
Tulika Seth: But it’s a mutation that you develop over time and due to this mutation…
Sohini Das Gupta: Okay…
Tulika Seth: …there is a BCR-ABL protein which is a tyrosine kinase and this tyrosine kinase causes increase in the white blood cells.
Sohini Das Gupta: Okay. Okay. Okay. Over to you Dr. Desai, since she mentioned that it’s an acquired mutation. What other factors at play here?
Desai: This is genetic change happening after the burn. And there’s no specific cause for this. The cells usually divide and they should have a normal genetic changes, but because of some reason these changes are abnormal in the body and that list to the chronic-myeloid-leukemia. There are very few non-risk factors for the CML and most of those cases you don’t find any cause.
Sohini Das Gupta: Okay.
Desai: Very occasionally there is high dose radiation exposure. Say, the survivals of atomic bomb blast or the nuclear reactor accident, but usually in majority of the patients we don’t know the cause.
Sohini Das Gupta: Okay. So Dr. Bhurani just to be clear, there are no lifestyle factors that we can keep in check to stay away from this particular disease then?
Dinesh Bhurani: That doesn’t seems to be affected by any lifestyle factors like smoking, diet, exposure to the chemicals or impact and even it is not genetic. So I cannot say everything you can do it to prevent CML.
Sohini Das Gupta: Okay. So that’s the bad part. Now onto getting to know the disease, so it can be combated. Dr. Seth, what would be the most common symptoms of this disease?
Tulika Seth: The commonest symptoms are a fever, increase in fever and heftiness of the abdomen. So many times the symptoms are very mild, but that person is asymptomatic and they get a blood test done than you don’t want to find the blood test.
Sohini Das Gupta: Okay.
Tulika Seth: So the symptoms are usually very mild and insidious. Sometimes patients who come to us very late they may have a very big enlargement of the spleen and low blood counts, but that’s usually if they’ve neglected themselves for a long time.
Sohini Das Gupta: So since Seth can you know, appear without any symptoms would you recommend like something like an annual check up or you know, something to keep a tab on where you stand with regard to the disease?
Tulika Seth: This disease does occur more in older patients.
Sohini Das Gupta: Okay.
Tulika Seth: So as you get older, it’s a good idea to get a good check-up – at least an annual check-up and a simple blood like the CBC can tell you that something is a problem. So yes, that will definitely help.
Sohini Das Gupta: Okay, and particularly for any one gender or both genders are equally susceptible?
Tulika Seth: Its slightly more suspect in male, but both genders are affected.
Sohini Das Gupta: Okay, okay. Dr. Bhurani, can you break down the process of diagnosis for us?
Dinesh Bhurani: Most of the patients are — most of the people are getting the blood test routinely. So some times, you go for the routine test, you don’t have any problem and the routine test tells you your white cell count has increased. And someone has seen the slide and that shows there are immature white cells are there in the slide. So many times, it may be that just the routine test may pickup your disease. Sometimes you have some symptoms like Dr. Tulika said describe it and you do the blood test, your white cell count has increased, your platelet might be increased and then someone sees the slide and there will be an immature cells under blood.
But once you have speaking of CML, you usually – ideally should go a bone marrow test. That is called a bone marrow aspirate and bone marrow biopsy. And simultaneously they do one of the chromosomal test is called cytogenetic test. Sometime the doctor may not order your bone marrow and do another test; it’s called FISH test or PCR test. So there are various methods to diagnose it. One is cytogenetics from the bone marrow. The others are FISH test or PCR test on the blood.
Sohini Das Gupta: Okay, okay. And you know the first response of a patient when you tell them they have any kind of cancerous disease is panic. So as a doctor, what would be your — like ward of assurance — an honest evaluation of how CML can be treated? And in what stages it’s treatable? Dr Seth?
Tulika Seth: We have done is chronic disease. So by definition, it is a disease that will last for a long time. And now we have very new effective molecular targeted treatments. So I just talked about the BCR-ABL protein and Dr. Bhurani said that we do a PCR test to diagnose this protein and the tyrosine kinase which is the protein which causes the proliferation, we now have a tyrosine kinase inhibitor, so there are many drugs in this route that can actually act on those cells and stop the proliferation. And in fact they are so effective that they can actually cure the disease. So these are tablets and they’re targeted therapies and because this is one of the few cancers where they have one mutation, the treatment is very effective. So at the moment in India, we had three of these drugs that are available. The first one, which is the oldest one is called imatinib and that has being available for many years. And we now have two newer tyrosine kinase chimeric and nilotinib dasatinib which is more of active then imatinib and all three of them are available in our country and we use them in our patients. And with these oral tablets which they just have to take at home. They can be cured of their diseases and in fact they’ve taken now to show that the life expectancy of patients of CML taking the medicine is almost the same – that this is not one of the leukemias and even in the West, the incidence is very high because most patients even though they are diagnosed with leukemia will continue to live. And here is the number of these patients are increasing and these patience can not only cure they can have good quality of life.
Sohini Das Gupta: Okay. Okay. Okay. Taking a cue from that Dr. Bhurani, would you explain the various stages of CML medically. So what happens when you – when the body progresses in the various stages of CML?
Dinesh Bhurani: CML has three stages. Majority of the patients more than 95% of the patients diagnosed in the chronic phase. So that’s a first phase. The second is accelerated phase. The third one is the last crisis. So there are three stages. Majority of the patients will be diagnosed in the first phase, which is a chronic phase, if they continue to take the treatment properly and have a regularly follow-up with the test is called PCI test and they found to have a satisfactory results. They will be in a first stage. It is become chronic diseases like a hypertension and thyroid disease that you can keep taking the drug and you are in the early stage of the disease. Someone who doesn’t take the tablet and misses his tablet, or if he doesn’t get the regular test done can go to the second phase or third phase. And once they reach to the third stage, the chance – then the survival becomes grim. So the – all effort should be to take the tablet regularly, have a monitoring regularly and try to keep your diseases in first stage. If it goes to the second or third stage then there are problems with the patient life.
Sohini Das Gupta: Okay. But its very essentially curable and combatable you can cure CML is what we are taking away from this?
Dinesh Bhurani: It’s the chronic disease – you need – sorry, you continue, sorry, sorry.
Sohini Das Gupta: Yes, Dr. Seth, yeah.
Tulika Seth: There are very few patients at the moment that we can absolutely cure. When we talk about cure, we mean that we can stop the medicine. So at the moment there is a lot of research and a lot of discussion in the medical fraternity about looking at these very good patients who have very good response and they – maybe some patients who we can cure that is that we can actually stop the medicine and they can continue to be without the disease. But the majority of patients just as Dr. Bhurani very rightly said, it’s manageable. So like you have hypertension, you will continue to take your medicines and continue to take — go for checkups. You essentially are not cured of hypertension. So in the same way, you have to take your medicine and monitor your PCR and your disease can be under control.
Sohini Das Gupta: Right, right.
Tulika Seth: That happens with the majority of patients and hopefully in the future we have some patients that we identify who can be cured and be off the medicine and to often there are very few patients who are off the medicine. Every doctor has maybe a few patients who are off medicine but…
Sohini Das Gupta: Okay. Okay. Dr. Bhurani drawing from what Dr. Seth said, she said that you have to live with the disease. You can keep the tab. You can manage and control it and keep it under check. So what would be living with the disease like? Is there an optimistic view into that like — are there side effects to your medicines that you are taking or do you have to compromise on certain areas of life? What is living with CML like, once you are in remission? I think we lost Dr. Bhurani. Dr. Bhurani, can you hear us?
Tulika Seth: Should I go ahead with the answer or — wait.
Dinesh Bhurani: You can. You continue.
Sohini Das Gupta: Sure, you can. Yeah. We lost both of them. The screen soars. I think it’s from our end.
Tulika Seth: Try and connect.
Sohini Das Gupta: She is still speaking.
Tulika Seth: Yeah, yeah. Dr. Dinesh said that we can go ahead with the answer — with that. Please try and connect them. Dr. Dinesh. Okay, let me just —
Male Speaker: Yes?
Sohini Das Gupta: Hi. We’re back.
Male Speaker: Yeah, yeah. Sorry.
Sohini Das Gupta: So no — this is a question that you know anybody who’s on the other end of the doctor’s table would be curious about. So I’d like both Dr. Bhurani and Dr. Seth to answer it from your own perspectives, what is the optimistic part of life after remission, after having gone through CML, how is living with CML. Is there any hope there?
Tulika Seth: Yes. Now there is very good hope. Majority of patients just have to take one or two tablets a day and the majority of patients do not have many side effects. Some side effects are there. Some side effects can be like fluid retention, some acidity, often these — and some aches and pains, but many things these side effects can be manage very well.
Sohini Das Gupta: Great.
Tulika Seth: Some they who have problems with one tyrosine kinase inhibitor but fortunately since we have three tyrosine kinase inhibitors, we can switch this and that is permitted by the medical evidence to switch patients according to their side effects from one TKI to another TKI.
Sohini Das Gupta: Okay.
Tulika Seth: That is thing that we do and even ladies who are pregnant can have children while they are on CML treatment but we have to be careful because we have to stop the TKI monitor the disease, put them on some alternative treatment and we have many families where they’ve been able to complete their families — patient and have the disease which they are under treatment.
So it is not a very mistake, but patients have to be regular with their medicines and they have to follow-up with the doctors, and in case they are planning a family, they should then discuss that with their doctor for what is the best time to took that and how they should manage their disease during pregnancy?
Sohini Das Gupta: Okay. Dr. Bhurani, would you care to elaborate on that how the formal patients and living with CML can be a perfectly doable thing and it’s not so scary after all?
Dinesh Bhurani: Provided we take the medicine regularly, provided we do the regular testing as been prescribed by the doctor. We go for the regular visits. It is similar to like treating hypertension and thyroid treatment.
So the many people who are on the sugar tablet, blood pressure tablet and the thyroid tablet and still going on the normal life. So probably we had to have a normal life with the medicine, with the regular doctor visits and the regular testing.
Sohini Das Gupta: And how about cautions that should be taken from the doctors end?
Dinesh Bhurani: Say it again?
Sohini Das Gupta: How about cautions or measures that should be taken from a doctor’s end to ensure that…
Dinesh Bhurani: This patient needs to have a BCI, that the BCI test done on the regular interval. Initially it is every three months then once you achieve a certain level then it is every six months and that target we need to achieve.
We need to determine the patient is taking the medicine regularly or not. He understands their importance of taking the medicines. He regularly take interest in the various parameters, the things should be fine.
Sohini Das Gupta: Okay, okay.
Dinesh Bhurani: Hello?
Sohini Das Gupta: That’s truly wholesome discussion. My final question is to you Dr. Seth, is there an approximate timeline till which you have to be vigilant after you gone into remissions?
Tulika Seth: Okay. The initial one or two year’s is very important. There you have to be very, very vigilance and beyond that it depends on the patients. So some patients if they have a very good response and they go into what we call a major molecular remissions and these patients after about 10 months or two years, most of these patients will not progress.
But there’s really no time where you can be careless. You have to be very compliant with the medicines and you still have to check with the doctor, but generally once the disease is undetectable by the molecular test, the chance of it going into the second or third stage become very restless.
Sohini Das Gupta: Okay, okay. I’ll just – to open one last question, because I am curious about the stats. Of all the other instances of blood cancer, where does the – you know, where does CML stand? What does the stat say about CML in comparison with the other kinds of blood caner?
Dinesh Bhurani: This accounts for roughly …
Sohini Das Gupta: Yes, Dr. Bhurani.
Dinesh Bhurani: This accounts for roughly 10% of all the – this accounts for 10% of all the blood cancers. I’ll say it’s more – probably there is some indications this is more common than the other cancers, other blood cancers in India. But I don’t have a supportive data to say. The CLL, one is Chronic Lymphocytic Leukemia probably is more common and in western word and Chronic Myeloid Leukemia is more common in our.
Tulika Seth: There is some cancer registry data from India which suggest the CML is the commonest blood cancer in India.
Sohini Das Gupta: Okay, okay. And do we have a stat on the treatability? Do we have some statistics on the treatability vis-à-vis other blood cancer?
Tulika Seth: The treatability is very good. The majority of patients are alive and in the U.S. they actually say that by 2020 we will have more than 100,000 people who are living with Chronic Myeloid Leukemia.
Sohini Das Gupta: Okay, okay. So we – I suppose we can wrap-up on that hopeful note.
Dinesh Bhurani: But I have one question of notice that because this is a oral tablet many people starts skipping the tablet and they go on to the second stage and third stage and some of them may loose them because they loose their responsibility, they’ve been very casual with the medicines because of the social reasons or financial reasons. So though it is highly controllable disease…
Sohini Das Gupta: Okay.
Dinesh Bhurani: But sometimes we see patients who have been in the higher stage because of the irregularity in their treatment.
Sohini Das Gupta: Okay. So it’s controllable but not to be taken lightly is our final takeover, right?
Dinesh Bhurani: Correct, correct.
Sohini Das Gupta: Thank you so much, Doctors.
Tulika Seth: Thank you.
Dinesh Bhurani: Thank you.
Unidentified Speaker: Dr. Bhurani and Dr. Seth, thank you so much for having joining – joined us for this special initiative. I am sure we will keep m meeting often and you know sharing your knowledge in the public domain….