Expert Series: Dr Devendra Hiwase – more research needed for greater insight into MDS
“Every patient with MDS is different”, says Dr Devendra Hiwase, and that’s why he thinks every patient with this rare form of blood cancer should have molecular profiling.
“Currently, we don’t do molecular profiling on every patient, but I think we should be, so we can find out which treatment option is better for each group of patients, based on their biomarkers,” said Dr Hiwase, a consultant haematologist at the Royal Adelaide Hospital, Associate Professor at the University of Adelaide, and a Senior Research Fellow at the South Australian Health and Medical Research Institute (SAHMRI).
Myelodysplastic syndromes (MDS) subgroups
The majority of MDS patients are older; around 85% of them are older than 60 years of age.
“Aging-associated genetic changes is one of the risk factors for MDS, which is a rare disease, but with the ageing population, the incidence is increasing,” said Dr Hiwase.
“There are three different subgroups of MDS.”
The first of these specific MDS subgroups are people diagnosed with MDS who have had no prior cancer diagnosis.
The second group includes MDS patients who have survived an earlier cancer diagnosis after being treated with chemotherapy.
“We call that specific group, therapy-related myeloid neoplasms (t-MN),” Dr Hiwase explained.
“t-MN are poorly understood blood cancers with extremely poor outcomes causing early death in otherwise long-term cancer survivors. They account for 15-20% of cases of MDS and are expected to rise due to the increased use of chemotherapy and improved survival of cancer patients.”
The third MDS group, which Dr Hiwase calls “cancer survivors who develop MDS with no prior exposure to cytotoxic therapy (chemotherapy or radiotherapy)”, make up ~10% of MDS patients and “is under-recognised or not talked about much in the literature or on patient forums”.
“MDS is a dynamic disease, and the field is changing more now than in the last 10 years,” said Dr Hiwase.
Why Dr Hiwase chose a medical career and to specialise in MDS
“My father died with cancer when I was young and that was the day I decided to become a cancer doctor,” said Dr Hiwase, who was accepted into a highly competitive medical graduate program at the Tata Memorial Hospital in Mumbai.
During his training he preferred haemo-oncology to the solid cancers and got interested in MDS. He moved to Oman where he worked in haematology malignancies, predominantly in transplantation, before heading to Australia on a fellowship. From Sydney, he moved to Melbourne, then to South Australia to do his PhD in chronic myeloid leukaemia (CML) with Professor Tim Hughes.
“After completing the PhD, I decided to work on MDS as there was nothing on MDS in South Australia at the time,” said Dr Hiwase.
He visited international MDS centres of excellence in the UK and Germany and, in 2012, he started the MDS Research Group in Adelaide, and the South Australian MDS Registry. He also is on the steering committee of the national MDS and Aplastic Anaemia Registry.
“I work on MDS and AML because the diseases are very diverse, there aren’t a lot of treatment options, and a lot of work is required to improve outcomes for these patients, which I took as a challenge,” said Dr Hiwase.
The SA MDS Registry has a comprehensive collection of information on 2000 patients including clinical profiling, disease features, bone marrow reports, treatment history, and treatment outcomes. And for those patients who give consent, their bone marrow samples are held in a biobank.
“These samples can be linked with their clinical details which allows us to do research which means we can address multiple gaps in the literature including: (i) genetic predisposition to MDS, (ii) molecular understanding of different subgroups of MDS which helps in identifying novel drug therapies, (iii) association of regular blood transfusions with poor prognosis, (iv) high risk of RBC-alloantibody formation, (v) frailty, (vi) infection burden, (vii) understanding the burden of hospitalisation (viii), and cardiac issues,” said Dr Hiwase.
Is there a genetic disposition to MDS?
“Not every cancer patient develops MDS, so we asked… why does a very small percentage of cancer patients who were cured from their cancer develop MDS or t-MN?” said Dr Hiwase about one of the questions at the basis of his research.
And this led to the question of a genetic disposition to the disease.
“Are there people who are more prone to developing MDS than other people?” he said.
“We’ve found, in our study, published recently in Leukemia, that around 13% of people with MDS who have t-MN or MDS following another cancer without cytotoxic therapy, had a higher frequency of genetic predisposition to MDS.
“The frequency of damaging inherited mutations in cancer survivors with blood cancer is four-fold higher than in patients with just one cancer (13% vs 3%). This would suggest that personal history of blood cancer and another cancer (excluding skin cancers) should trigger assessment for damaging inherited mutations.
“There’s a subgroup of MDS patients who have a genetic disposition to the disease and that has significant implications for the patient and their family members also,” said Dr Hiwase.
Yet currently, he said, clinicians don’t look for a genetic disposition unless MDS is diagnosed in younger patients.
“However, we have identified that some patients with genetic predispositions are not diagnosed early in age but present at a similar age to MDS patients without genetic predisposition. We did not find a difference in the age of presentation,” said Dr Hiwase.
“Importantly, the National Comprehensive Cancer Network guidelines, and other guidelines, provide some recommendation on which patients should be tested for inherited genetic mutations.
“And some of the patients we tested could not have been flagged by this recommendation, which means the possibility of genetic predisposition should not be excluded just based on the patient being older and not having abnormal features.
“If there is a personal history of two cancers, one of them being blood cancer (excluding skin cancer) then genomic testing is helpful, and I think we should be considering that.”
Dr Hiwase said there were several reasons why genomic testing was important in these cases.
“If the patient is younger and fit for an allogeneic transplant and we want to transplant them, our first donor choice would be a HLA-matched sibling or family member, but not if the patient has a germline mutation.
“We don’t want to use an asymptomatic family member who also has the same inherited genetic mutation as the patient. We have to test the potential donor for genetic mutations to avoid this happening because it could be a disaster for the patient in the future.
“Secondly, the chemotherapy or conditioning chemotherapy we use may have to be changed for certain germline mutations.
“Number three, we have to have a surveillance plan to follow-up on patients, to look out for toxicity of the chemotherapy and other medications.
“Even though this is a small group of people among the total MDS population, as clinicians we cannot ignore this subgroup of patients who have a genetic predisposition,” said Dr Hiwase.
“There’s an ongoing debate among colleagues about whether we test everybody, or only some people, and how do we decide which patient is tested?
“Further research is required to identify which patients should be tested, and how we test them.”
Decision making around treatment options
Dr Hiwase said, currently, treatment decisions in MDS are made during a short clinical visit and based on a patient’s disease features – a high bone marrow blast percentage, abnormal chromosomes, and low blood counts.
The majority of older people with MDS have other health issues such as diabetes, heart, lung or kidney problems, and 30-40% are not as physically fit. Dr Hiwase describes this overall frailty as a “reduced reserve” and it affects their ability to fight infection and makes them more vulnerable to toxicity from the treatment.
“These patients sometimes may not benefit from the treatment,” he said.
His research in this area, published in 2020, showed that patients who are not fit, if treated with the standard therapy, may not tolerate the treatment or respond very well; they may not get a benefit from it because of their frailty.
“So we consider other treatments and clinical trials, and how to optimise their frailty.
“And there may be some patients who are better managed early with palliative care or supportive care,” Dr Hiwase explained.
“If treatment could potentially cause harm, whether to a patient’s quality of life, their survival or it places an increased burden on them, then don’t treat, focus on improving their quality of life by providing more supportive care.”
Identifying patients on the basis of their level of fitness, and not on their age, also means there are people in their late 60s and early 70s who are fit and shall be considered for stem cell transplant, depending upon their disease risk, other health issues, and organ function.
“In the past, we only transplanted younger patients. Then we started transplanting people up to 65, and more recently we decided to transplant patients 65-70 years of age based on their physical fitness and their organ fitness,” said Dr Hiwase.
“When making treatment decisions, older patients should be assessed more comprehensively, taking everything into consideration – their comorbidities and physical function, social and nutritional issues, not only their blood parameters and bone marrow finding.
“We need to treat the patient, not the disease only – that’s a key message for clinicians when making decisions about the best treatment for a patient.
“And patients need to discuss their other health issues, their social background and their physical function with their doctor, because ultimately it is the patient who makes the decision about their treatment choice, along with their doctor and their family members.
“Assessment of patients’ physical, social, nutritional, and other health-related issues can be challenging during a clinic visit with their haematologist,” said Dr Hiwase.
“Hence, at the Royal Adelaide Hospital, we have a dedicated nurse coordinator who navigates MDS/AML patients throughout their treatment journey and provides support.
“This involves performing multidimensional geriatric assessments, providing referrals to appropriate allied health services, and alerting the haematologist about their concerns. Patients can be referred to other specialists and/or a geriatrician if required.
“At our centre Michelle Wall, a senior nurse, has been in this role for the last five years and our patients love her,” said Dr Hiwase.
“Some patients have a really poor quality of life, but their family wishes them to have treatment to prolong the life of their dear ones, and the patient doesn’t want to disappoint their carer/family members.
“Thus, we as a team – haematologist, carer, and case coordinator – should listen to patients’ wishes rather than forcing our ideologies on them,” Dr Hiwase explained.
MDS risk groups and treatment options
When a person is diagnosed with MDS they are identified according to a risk group. Based on the International Prognostic Scoring System (IPSS-R) for MDS there are five groups: very low, low, intermediate, high, and very high.
Dr Hiwase said patients with high- and very high-risk MDS were generally treated with azacitidine (Vidaza®) which is available on the Pharmaceutical Benefits Scheme (PBS).
“Azacitidine is not a curative treatment, but it is currently the best available option and it can improve the outcome and provide benefit, on average, for nine months compared to traditional care,” he said.
“I have some patients who have been on this treatment for four to five years.”
Around 30% of patients do not respond to azacitidine within the first six months of treatment, approximately 15% of patients achieve complete remission, and 30% achieve stable disease on azacitidine.
Azacitidine holds the disease at bay, reduces the transfusion requirement, and improves the quality of life in some patients,” said Dr Hiwase.
But azacitidine does not cure, he said, and ultimately most patients fail azacitidine.
“Allogeneic stem cell transplant is a potential curative treatment but only 10% of MDS patients are referred for transplant, and the majority of MDS patients are not fit for it.
“Over the last decade or so, there have been no new therapies for high-risk MDS apart from lenalidomide (Revlimid®), which is PBS-approved and is very effective for a specific group of patients with the rare MDS subtype, deletion 5q.”
Dr Hiwase said venetoclax (Venclexta®), “which is the new kid on the block” has shown some improvement in treating AML and is available in clinical trials.
“We have some MDS patients who failed on azacitidine, their disease progressed, and they are doing reasonably on venetoclax, and one of my patients survived for 24 months on a combination of azacitidine and venetoclax,” he said.
Other targeted drugs have been helpful for patients with specific mutations, such as IDH1 and IDH2, but Dr Hiwase said mutational profiling was needed to identify targets so targeted therapies can be developed.
“MDS is a neglected area. We need more clinical trials and research in this area.”
Around 60% of MDS patients are considered to be lower-risk, and Dr Hiwase said, “the good news is that there are trials of newer drugs coming up” for these lower-risk MDS patients.
One of these drugs, luspatercept (Reblozyl™), works on red cell development and can improve the haemoglobin and reduce the transfusion burden. Another, magrolimab, is a monocloncal antibody against the CD47 antigen which is expressed by MDS cells at a high level.
“That particular protein gives the body’s immune system a ‘don’t-eat-me signal’. When we give the antibodies to that (magrolimab), we can dampen that signal, so the body’s immune system can eat it; that’s how that drug works,” said Dr Hiwase.
“It’s in a clinical trial now, and we are participating in that trial.”
His key message for patients is to ask their haematologist if there are any clinical trials available at their centre, “because there are always new drugs coming up”.
Dr Hiwase said there were some low-risk MDS patients who can progress quite quickly to higher-risk or even to AML, “and their outcome is poor”.
And a large number of patients, around 85%, require blood transfusions at some stage during the progress of their disease, and 50% of patients are transfusion dependent. They need a regular blood transfusion to improve their symptoms, such as fatigue.
“Some patients still feel very fatigued and tired despite having the transfusions and that could be due to the chemicals or cytokines produced by the MDS,” said Dr Hiwase.
For somebody who is having transfusions, it is standard practice for the donor blood to be matched to the patient’s ABO and Rh blood group.
“However, there are other different types of blood groups which we don’t check regularly, so there can be a mismatch between the donor and the patient,” said Dr Hiwase.
“If the patient gets a blood donation that is not matched for red cell antigens, they can develop antibodies, which can lead to difficulty in finding compatible blood quickly and can increase transfusion requirements.
“We have been working on this for three years and our research shows that 10-12% of MDS patients who get regular transfusions develop red cell antibodies, which is not tested at this stage.
“Because of our research finding at our centre in South Australia, we test for other blood groups, and try to give our patients more matched blood, to minimise the risk of antibodies,” he said.
Optimal care pathways (OCPs)
Dr Hiwase is on the Leukaemia Foundation’s MDS Optimal Care Pathways working group which is developing a guideline for the medical community – haematologists and doctors – to improve MDS patient outcomes in two ways; by minimising complications and optimising the outcome of current therapies and the development of new ones.
There are seven key principles of optimal care pathways: patient-centred care, safe and quality care, multidisciplinary care, supportive care, care coordination, communication, research and clinical trials.
“We have noticed there can be a significant delay in referring a patient to a specialist, so that delay can be minimised. The workup of patients needs to be improved, as well as access to drugs and to a specialist centre,” said Dr Hiwase.
Key questions to ask your treating haematologist?
Dr Hiwase said the first questions a patient newly diagnosed with MDS should ask at their first appointment with their haematologist is, what subtype of MDS do I have, what risk group am I in, and what are my treatment options?
At their next visit, in three months, the patient who is on watch and wait and doesn’t require any treatment at that stage should ask, how am I going, are my blood counts stable, am I progressing?
Once treatment has begun, a patient should ask if they are progressing to high-risk or whether their risk has stayed the same.
The patient who is having blood transfusions should ask their doctor, am I needing more regular transfusions, am I developing RBC-alloantibodies, am I getting iron overload, and is there a different option for me now that wasn’t available three months ago?
When a patient comes back at six months, they would repeat their earlier questions and ask, do I need to repeat the bone marrow biopsy process? And they should tell their doctor how many infections they’ve had and how many times they have required antibiotics since their last visit. This information will help their doctor decide how well they are coping and what else can be offered, such as erythropoietin.
A young MDS patient, aged 60-65 years of age, who is very fit, should ask, would you offer me a stem cell transplant?
“The answer initially may be ‘no’ because their disease is low-risk but we should be doing more blood tests to find their tissue type, or to find a donor in case a transplant is required in the future,” said Dr Hiwase.
Three months later they should ask, has my MDS progressed? And if it has, they should ask about being referred to a transplant centre.
The high-risk patient, aged 75-80, who is not fit for transplant, and lives alone, but who is still fit, should ask, what are my treatment options, what benefit would I get from them, and what is the toxicity of the treatment? Once on that treatment, at their monthly visits, they should ask about side effects. Also, am I responding to the treatment, am I tolerating it? And they should tell their doctor about anything that is bothering them.
Patients with specific chromosomal changes, such as del 5q, should ask about treatment options that are available and, are there any clinical trials that you can offer me that I can consider?
What Dr Hiwase would do if he was diagnosed with MDS?
“I would find out which is the nearest specialist centre that looks after patients with MDS,” he said.
“If I was in a country town, I’d find out how far away that centre is and how far away from me is the community’s haematologist?
“Then I would ask my GP to refer me to the haematologist and I would see them.
“I would ask my haematologist, what is my risk and what are my treatment options? I would take that information and go home to my wife, or to a friend for discussion. Then I’d go back to the doctor and say, I’d like to consider this and this option, can you give me more information?
“Once I’m satisfied I’ve got all the information I need and I’m ready to make a decision, I’ll make that decision in consultation with my haematologist about which is the better option for me, and I will go with it.
“If one of the options is a clinical trial and if it’s available to me, I’ll request to be considered for the research study, and I would duly consider if it’s right for me or not.
“When I make a treatment decision, I would also consider whether it would improve my quality of life or whether the medical visits and hospitalisation would be a burden on me and my family.
“Importantly, I’d see where the research is going and what new treatments were coming up.”
Key advice from Dr Hiwase
Dr Hiwase said he gives his patients assurance that while their MDS journey may be long and one which they have to take, he will support them throughout their journey with his knowledge and ongoing discussions with them.
“They should not panic. They should not worry too much and don’t do too much Dr Google, which can give a very daunting picture,” he said.
“I would provide them with links of where they should go to look for appropriate information, for example, the Leukaemia Foundation’s website.
“My key advice to them is that not every MDS patient is the same. There is significant variation in the disease, so work with your haematologist to find the right treatment for you.
Dr Hiwase’s holy grail
“The one thing I want to achieve in my life is to improve the outcome of the MDS patients and prevent t-MN, to improve their survival and quality of life by optimising the current treatment and developing new treatments for them,” he said.
“It can only be achieved through clinical and translational research.”
Acknowledgement by Dr Devendra Hiwase
“I would like to thank you, my patients, and their families for trusting me to be a part of their difficult journeys.
“I also would like to acknowledge my mentor, local and international collaborators… without their help we could not do the research: A/Prof. Chris Hahn, Prof. Hamish Scott, Prof. Lucy Godly, Prof. Timothy Hughes, and A/Prof. Daniel Thomas, Dr Deepak Singhal, Rakchha Chhetri, Monika Kutyna, and Amilia Wee.
“And lastly, my wife and children, who have supported me throughout my life in my journey.”