Naval Daver, MD

There are several exciting new therapies that are in phase 1/2 and phase 3 studies now in MDS [myelodysplastic syndrome]. I would say in the last 4 to 5 years, we have now more exciting drugs than we have had in the prior 2 decades for MDS. I think part of this is because we are seeing a lot of the drugs that have been recently approved in the acute myeloid leukemia [AML] space, now moving to the myelodysplastic syndrome space. These include a drug called venetoclax, which in combination with hypomethylating agents [HMAs] like azacitidine and decitabine, showed dramatic improvement in response rates in older, unfit patients with AML, with a response rate of 70% CR [complete response]/CRi [complete response with incomplete hematologic recovery] compared to 30% with azacitidine alone. It has been approved in the combination of azacitidine/venetoclax in frontline older, unfit AML.

We know that the biology, especially in patients with MDS with high blasts, can be quite similar to AML in the older, unfit population. This has now led to studies of azacitidine/venetoclax in MDS with high blasts, which have shown very encouraging response rates, close to 80% overall response, and 40% to 45% true CR rates. This has led to a randomized phase 3 study looking at azacitidine/venetoclax versus azacitidine therapy in frontline, higher-risk, high-blast MDS. Given the success and the efficacy of this combination in older, unfit AML, we are hoping it will also have a similar efficacy and have a good shot of being approved for MDS.

Another new drug that is also very exciting is pevonedistat. This drug has been evaluated in combination with azacitidine, both in a single arm and randomized phase 2 study. The data show that the response rate of [azacitidine]/pevonedistat is very encouraging, especially the true CR rate of close to 50%. In a randomized study, especially in higher-risk MDS, there seemed to be a very strong trend toward improvement both in event-free and overall survival. This has led to another large phase 3 study called PANTHER, it just completed enrollment, of [azacitadine]/pevonedistat versus [azacitadine], about 6 months ago. We’re hoping by the end of this year we may see the results of that study, which again could then lead to the approval of azacitidine/pevonedistat in the older, higher-risk MDS population.

Then there’s a fourth drug called sabatolimab, which is also an immune drug. Unlike magrolimab, which works on the innate immune system and the macrophage system, the sabatolimab seems to work more on the T cells, blocking TIM-3 and activating T cells. This is also now in a randomized phase 2 study and has shown some very promising responses and activity in the prior phase 1/2 study. This especially seems to be good at improving the duration of responses and was very well tolerated compared to many other immune checkpoint antibodies we have tried in MDS and AML.

I think the big question is, let’s say, if all 4 of these drugs get approval in the next 1.5 years, how will we optimally use them? There are now some hints of how this will happen coming from the molecular and cytogenetic analyses of these ongoing phase 2 studies, where we’re seeing, for example, magrolimab/azacitidine seems to work really even in 

 and adverse cytogenetics. It works well across the board, but it seems to work well in this high-risk group, where almost nothing else works. If I have a patient with 

-mutated AML or adverse cytogenetics, I really am trying to get them on azacitidine with the CD47 SIRP-alpha, such as magrolimab, because we know venetoclax and others may not work as well. On the other hand, if I have a patient with MDS with an 

, based on the knowledge we have from AML, we know [azacitadine]/venetoclax could have a very high response in that population, and we may consider it.

I think as we do more molecular analysis and cytogenetics, we will find that there will be different populations that could benefit specifically from one of these combos. Then the next step is how can we optimally combine or sequence these drugs? For example, if [azacitadine]/magrolimab and [azacitadine]/venetoclax are both approved, could we consider doing [azacitadine]/venetoclax/magrolimab to really improve the depth of remission, the molecular and MRD [minimal residual disease] clearance, and the survival? A lot of these are already starting as phase 1 trials while we’re waiting for the readouts from the doublet phase 3.

I think if all goes well, just like in AML in the last 4 years, the complete landscape and treatment approach could change very dramatically and in the benefit of the patients and the clinical research for MDS. We’re looking forward to that.

My main advice would be to recognize that there is a lot happening in both MDS and its related disease, acute myeloid leukemia, compared to 10 years ago when we really had not had any major drug approvals and major changes in molecular and immune therapies. Today there has been a huge shift in the treatment, and a lot of these treatments are significantly improving response rates, survival, and are often as tolerable or even better tolerated than the previous therapies.

In addition, I would strongly consider thinking about clinical trial options for the patients, especially because today all the 4 or 5 most exciting drugs in frontline higher-risk MDS are all available mainly through clinical trial. If you have a patient who has higher-risk MDS and is willing to travel, they may really benefit quite significantly by going onto one of these frontline trials. Often, we get a huge number of patients for trial referrals, and we will keep them here for the first cycle, which is usually the first month. Then for the subsequent cycles, we usually work closely with the community or local oncologist. The patient comes back here for 1 or 2 days for clearance to start the next cycle, and then the rest of the blood work, monitoring, and even treatment is done locally. If you have local academic centers that are willing to work with you, this could be a great option for your patients to get access to these novel combinations that may not yet be fully approved for a little while, but they are showing very exciting responses and data.

Lastly, even in patients who have failed traditional and standard HMA therapies, there are now other new immune therapies and oral therapies that are emerging that could be of high interest. You should consider these options, and maybe again have a discussion with your colleagues in the large academic centers close to you, or any time feeling free to reach out to us; there are now many trials developed in post-HMA with NK [natural killer] cells, CAR T [chimeric antigen receptor T-cell therapy], bispecific antibodies, others, that could be an option if your patient is willing to travel. All in all, I think the future is looking bright. We will hopefully continue to make rapid strides and progress in improving the outcomes for patients with high-risk MDS. Thank you for listening.

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An oncologist discusses the future of myelodysplastic syndrome, including upcoming studies and potential treatments.

The Future of Myelodysplastic Syndrome

There are many new emerging treatments both for low-risk MDS [myelodysplastic syndrome] and high-risk MDS. Especially in high-risk MDS, in the last 3 to 4 years, there’s been dramatic progress with a number of drugs showing very exciting activity. These include immune activating drugs like the CD47-targeting antibody such as magrolimab. Also, there are drugs that seem to improve the apoptosis and have been approved in AML [acute myeloid leukemia] such as venetoclax, other new therapies activating the immune system such as TIM-3 antibody sabatolimab, and drugs like pevonedistat that work through unique neddylation pathways. All 4 of these drugs, in combination with azacitidine, are showing very promising activity. In fact, all 4 are in randomized phase 2/3 studies, and we’re hoping that either all 4 or many of those will meet their end points and change the entire frontline treatment of MDS very rapidly within the course of the next 1 to 2 years.

Among these, one that we’re very excited about is an agent called magrolimab, which targets CD47. The biology and mechanism of action of this therapy is unique to anything we have used in leukemia, in fact, for that matter, to anything we have used in solid tumors. We have been very familiar for many years with the concept of immune checkpoint blockade for T cells; blocking PD-1 on the surface of the T cells and PD-L1, its ligand, on the surface of a cancer cell, we remove the brakes on T cells, and the T cells come out from their exhaustion and become active and attack cancer cells. This has been very successful in many solid tumors and resulted in major breakthroughs in the treatment of those cancers.

However, we were not able to get the same degree of success with immune checkpoint-based therapies in AML and MDS despite efforts to try many different immune checkpoint approaches. What was started to be identified is that it may not be the T cells, but the macrophages that are major mediators of anti-tumor activity in both MDS and AML. This led to the development of an antibody that blocks the CD47 SIRP-alpha axis, CD47 present on the surface of cancer cells, and SIRP-alpha on the surface of macrophages. This also suppresses the macrophages by giving inhibitory signals. By blocking this axis using an antibody, we are now seeing that the macrophages are reactivated, rejuvenated, and very effective at seeking and attacking and killing MDS as well as acute myeloid leukemia cells.

This unique mechanism of action and the fact that CD47 is expressed at very high levels in almost all molecular and cytogenetic subsets of MDS led to initial phase 1b studies combining azacitidine with magrolimab. These have been presented by [David] Sallman, [MD,] and myself at multiple meetings over the last couple of years, where initially in MDS and then in acute myeloid leukemia in the frontline setting, the combination of magrolimab with azacitidine has shown very striking responses. Especially in MDS, we see the overall response rate is close to 85%, 90%, including a true complete remission with full recovery of count rate of about 45%-50%. To put this in perspective, the expected true complete remission [CR] rate with azacitidine alone is about 20%, so 45% to 50% is more than double.

The very nice aspect with this therapy has been that it has been overall safe and well tolerated. The only issue that we can see, and this is very time dependent during the first 1 to 7 days of treatment, is an on-target anemia. Anemia occurs because CD47 is expressed heavily on the surface of the red blood cells, especially the older red cells. When we initially give the CD47, the older red cells are coated with it, and they’re removed by the reticuloendothelial and the splenic system. We see initially, after the first or second dose, there can be a drop in hemoglobin. The usual amount of drop is between 0.5 to 1.3, 1.4 [g/dL]; not severe, but of course one must monitor and transfuse. Remember, these are older patients with MDS, and they may already be starting at 8.59 [g/dL]. It could drop to 7.0, 7.5 [g/dL], and those patients may need transfusions.

Other than this anemia, which we recommend very strongly to monitor for, I usually would suggest doing blood work daily or every other day during that first 6- to 7-day period, after which it appears that the CD47 is pruned off the surface of red cells and we no longer see that anemia. Other than this anemia, it’s an overall well-tolerated therapy. We do not see mucositis and nausea, vomiting, diarrhea, and we do not see many GI [gastrointestinal] adverse effects or musculoskeletal issues. In fact, we do not see much neutropenia or thrombocytopenia, which is I think one of the positive aspects of this agent compared to some of the others. We do see some infusion reactions in about 10% to 15% of patients, usually grade 1, and they can be mitigated with the use of steroids, and Benadryl [diphenhydramine], if needed.

At this point, the drug is being evaluated in a phase 3 randomized study called the ENHANCE study. This is of azacitidine alone, which is the standard of care in the United States, approved by the FDA and NCCN [National Comprehensive Cancer Network], versus the combination of azacitidine with magrolimab. The primary end point of this study is improvement in both the true CR rate and overall survival rate, and we hope to have the top-line results from this study in the next 1 to 1.5 years. If positive, of course it will result in the approval of this combination for the frontline treatment of MDS in the US and ex-US sites.

Dr. Naval Daver provides insight on the emerging first-line treatment options for high-risk myelodysplastic syndrome and breaks down clinical trial data.

Emerging First-Line Treatments for High-Risk Myelodysplastic Syndrome

 Each year, of all the patients with MDS [myelodysplastic syndrome] in the United States, about 55% to 60% will present with a higher-risk MDS. We generally consider, using the IPSS-R [Revised International Prognostic Scoring System], anybody who has intermediate, high, or very high, any of those 3 categories, to be among the higher-risk MDS population. For this patient population, the goals of treatment are 2-fold. No. 1 is to control their disease. Many of these higher-risk patients will come with high blasts and are in a transition, transforming to acute myeloid leukemia [AML]. The first goal is to reduce the bone marrow blasts and get them into what we call a bone marrow remission, meaning less than 5% bone marrow blasts. This should slow the MDS progression and ideally prevent or at least significantly delay the transformation to acute myeloid leukemia by many years. This will be very important because it will improve the long-term overall survival of the patient.

The second goal is the same as in lower risk, which is to reset the normal hematopoietic equilibrium in the bone marrow, to start producing healthy and higher amounts of red [blood] cells, platelets, and white cells to mitigate the cytopenias that are seen; these are usually even more severe in the higher-risk MDS.

How do we achieve these? We have different treatments in the high-risk MDS. The most used drugs in the United States and probably in the world for the higher-risk MDS populations are a group of drugs called hypomethylating agents [HMAs], or demethylating agents. These are not traditional cytotoxic chemotherapy; they’re not designed to kill cells like we use chemotherapy for in many solid tumors, but are actually epigenetic-modifying drugs. These have been approved about 15 to 18 years ago. Many of the studies that led to their approval were led by investigators at the [University of Texas] MD Anderson Cancer Center at that time; these studies showed a response rate of about 30% to 40% complete remission or marrow remission with hematological recovery in patients with high blasts, higher-risk MDS. These are also associated with an improved survival compared to the traditional therapies such as hydroxyurea, observation, or growth factors that were available at that time. These are probably the bread and butter of treatment. However, 35%, 40% is not ideal; a lot of efforts are ongoing to improve that response rate by adding other drugs—immune drugs, targeted drugs, apoptosis-stimulating drugs—to that backbone of HMA therapy.

Now there are a couple of caveats. We do sometimes consider traditional induction cytotoxic intensive therapy for patients with MDS; who are those patients? Those are usually patients who are younger, below 65 years of age, and present with high blasts, above 10%, 15%. They’re very close to AML, and often the biology and the mutations are very similar to AML. In those patients, when we’re going for curative intent with a hope to get to a stem cell transplant quickly, we may do intensive induction chemotherapy approaches, rapidly followed by allogeneic stem cell transplant after 1 or 2 cycles. In addition, there are certain mutational groups we have started to identify of MDS that behave like AML. This includes patients with 

 mutations, and then those with inversion 16, 8;21 translocations, core binding factor, or with 

 translocation 15;17. These 5 or 6 groups of patients, even though they may have 15%, 10%, even 5% blasts that look like MDS, have biology and response to therapy similar to AML. We treat them with AML-like therapies irrespective of the blasts, and these are called AML defining mutations or cytogenetic abnormalities.

After doing the treatment, whether it’s with hypomethylating epigenetic therapy, a single agent or combination, or with intensive chemotherapy, the goal is to get these people to allogeneic stem cell transplant. If we achieve remission but we cannot go to transplant with the therapies in higher-risk MDS, the duration of response is usually between 6 and 18 months. It is not long term and not curative. Usually, the goal is to transition these people in remission, in a very controlled condition, with count recovery and often in a better physical state to allogeneic stem cell transplant, which then often is curative.

There are some patients who are not eligible for allogeneic stem cell transplant, in which case then we would continue the hypomethylating agent epigenetic therapy. I do have patients who have been on epigenetic therapy for 5 to 10 years and are ongoing if they are not transplant candidates, do not have a good donor, or are too old for allogeneic stem cell transplant. This is kind of the general landscape of treatment for the higher-risk MDS population.

An expert details the treatment options for high-risk myelodysplastic syndrome.

Treating Patients with High-Risk Myelodysplastic Syndrome

 For low-risk MDS [myelodysplastic syndrome], the goal of treatment is to improve the blood [cell] counts. The main clinical issue in low-risk MDS is the presence of cytopenias, meaning low counts, anemia, thrombocytopenia, and neutropenia. And about 35% to 40% of all newly diagnosed MDS in the United States will fall into one of the lower-risk criteria by the IPSS-R [Revised International Prognostic Scoring System], including low and very low risk. These patients usually do not have a high blast [percentage] in the marrow; they are not at impending risk for transformation to acute myeloid leukemia [AML] or becoming proliferative. However, the main issue is that because of anemia, they may have fatigue, weakness, shortness of breath, high risk of cardiovascular or CNS [central nervous system] complications because of neutropenia, and they’re at risk of infections, and because of thrombocytopenia they’re at risk of bleeding. Sometimes these patients may need frequent blood or platelet transfusions to keep their numbers up, which of course, has a major impact on quality of life as well as financial implications and time spent in the clinic.

The goal of treatment of low-risk MDS is really to reset the bone marrow by removing or reducing the dysplastic changes as much as possible and stimulating the production of normal red cells, platelets, and white [blood] cells. The treatments are usually a very low intensity therapy because we’re not really trying to kill large amounts of leukemia or cancer cells here, but it’s really more treatment to reset the bone marrow. For patients who have low hemoglobin, we often will check the erythropoietin level.

Erythropoietin is a hormone that helps stimulate hemoglobin; if the erythropoietin level is less than 500 [mU/mL], we can often use growth factors called erythropoietin-stimulating agents. Drugs like Procrit [epoetin alfa], Aranesp [darbepoetin alfa], and others can help bring the hemoglobin up in about 50% to 60% of patients and make them transfusion independent. Usually this could last for 1 to 4 years. Now there are also new drugs, such as luspatercept, that work through unique ways to stimulate production of hemoglobin; they seem to work even in patients who have failed erythropoietin-stimulating agents. These have been recently approved and are available. For patients who predominantly have problems with low white [blood cell] count and low neutrophils, putting them at a high risk of infection, then using growth factors that stimulate white cells, such as Neupogen [filgrastim] and Neulasta [pegfilgrastim], could be considered.

Then we have a big group of low-risk MDS that has hypoplastic or aplastic changes; they have low cells in the bone marrow to begin with, and we are trying to stimulate the overall bone marrow to have more cells and produce more hemoglobin, platelets, white cells. For this hypoplastic/aplastic MDS sort of scenario, we can use immunosuppressive therapy like cyclosporine, cyclosporine/ATG [antithymocyte globulin], cyclosporine/ATG/steroids; they seem to work quite well.

There is also a third type of unique low-risk MDS called MDS associated with deletion 5q. In some cases, this is an isolated deletion 5q chromosome abnormality, in some cases it’s a deletion 5q with other abnormalities. These patients seem to respond very well to an oral therapy called lenalidomide or Revlimid. Especially in the isolated deletion 5q, their complete hematologic response rate to lenalidomide is almost 65% or 70%; it’s not as high with those who have deletion 5q with other associated abnormalities, about 35%, 40%. Therefore, we would consider the use of lenalidomide in patients with a known deletion 5q.

Now transplant is very tricky especially in low-risk MDS. Bone marrow transplant, also called allogeneic stem cell transplant, is really the only curative option for MDS and in AML, both in low risk and high risk. However, this procedure is a very major procedure. It does have a high risk of complications, including acute and chronic graft-versus-host disease [GvHD], and potential mortality from post-transplant infections and severe forms of the GvHD. We almost never will transplant lower-risk MDS because these patients can have a median survival anywhere from 5 to 10 years; often these are older patients, 65 or 70 years old, so exposing them to transplant may actually cause more damage and more harm than benefit.

We are now learning that even those patients who are at lower risk due to having lower blasts and not as severe cytopenias, may still have mutations like 

, that could actually put them at a higher predictive risk of transformation. Now we are restructuring the MDS risk scoring, and soon we will be seeing an MDS IPSS scoring system that incorporates molecular information. This may move some of the patients with traditional lower-risk MDS to higher risk just based on the presence of their mutations.

Naval Daver, MD, illustrates the goals of treatment and treatment options for low-risk myelodysplastic syndrome.

Treatment Options for Low-Risk Myelodysplastic Syndrome

 The diagnosis of MDS [myelodysplastic syndrome] is made by a test called a bone marrow aspirate and biopsy. The bone marrow usually will let us know the percentage of blasts in the marrow. This is usually identified initially by a pathologist reviewing the bone marrow using a special stain under microscope. If there are increased blasts, between 5% and 20%, then this will usually suggest a diagnosis of MDS. Of course, we’re also looking for dysplastic or morphological changes in the bone marrow in addition to this, which helps us support the diagnosis of MDS.

In addition to just knowing if a patient has MDS or not, we really want to know what the chromosome and molecular state of the patient is, because there is no longer a one-size-fits-all therapy for MDS. The therapies are really tailored based on the underlying molecular mutations, and we now have targeted therapies both in MDS and AML [acute myeloid leukemia] for several different mutations. If patients have a 

 mutation, we have FLT3 inhibitors that are very effective, whether given as a single agent or in combination with other drugs. If they have an 

 mutation, we have IDH1/IDH2 inhibitors, which are also very effective. If they have a 

 mutation, then standard therapies often do not work, and we may consider using novel therapies like CD47 or other immune-based approaches.

In addition to knowing if a patient has MDS, what is the blast percentage, what is the degree of dysplasia, which cell lines are dysplastic, at the [University of Texas] MD Anderson Cancer Center we usually send off a large molecular panel, we call it the 81-gene panel, that will give us a lot of genomic information that has both prognostic value and also predictive value in selecting the best treatment. As we discussed initially, cytogenetics are the most important for the prognosis, so we also want to get that cytogenetic information very early.

When we are checking for cytogenetic and molecular features in a patient, usually the first thing we will have available is the cytogenetic information. There are 2 ways to look at cytogenetics. One is by what we call routine karyotype, which provides the entire cytogenetic information for the chromosomes of that patient. Second is what we call a FISH [fluorescence in situ hybridization] probe that will look at specific targeted cytogenetic abnormalities, usually ones that are known to be most common in MDS.

The IPSS-R [Revised International Prognostic Scoring System] usually buckets these cytogenetic abnormalities into 3 big groups. One is called a favorable group; this includes patients who have cytogenetic abnormalities like deletion 20q. The next is an intermediate group, and then there’s the unfavorable or high-risk group that includes cytogenetic abnormalities like deletion 5, deletion 7q, deletion 17, and chromosome 1 and 3 abnormalities. Everything else falls into the intermediate group. At our center, we usually try to get this information within 3 to 5 days, and it helps us understand if this patient has favorable, intermediate, or adverse cytogenetics. This also plays into the eventual IPSS-R score, and the decision about whether we will be considering allogeneic stem cell transplant for that patient.

The second piece of information is the molecular mutation information; this takes a little bit longer, about 5 to 6 days for us to get the full 81-gene molecular mutation panel. In this, the 5 or 6 important mutations we’re looking for are 

 rearrangement, and now new mutations like 

, for which also there are targeted therapies. We usually find in about 20% to 30% of patients a targetable mutation that will change our initial therapeutic decision, moving us to a targeted therapy combination, which usually has a better outcome if there is a targetable mutation. These are the 2 important sets of information.

One of the things we have noticed often in patients coming to us from smaller community sites, is they may not have the full mutation information, or they may have very limited mutational data. Often, we are able to pick up mutations that were not known or identified outside that actually change the treatment choice by giving us a new target that has been identified. I think getting this information is really critical to selecting the treatment choice.

A key opinion leader describes how myelodysplastic syndrome is diagnosed, the typical presenting symptoms, and the methods of risk assessment.

Diagnosis of Myelodysplastic Syndrome

Myelodysplastic syndrome [MDS] is a hematological malignancy associated with bone marrow dysplastic changes that result in a decrease in production of different bone marrow cellular components, including red cells, platelets, white [blood cell] count. The main complications we see with myelodysplastic syndrome are related to the decreased production of different hematopoietic components. Due to the low white count, patients are at risk of infection, and low hemoglobin will result in anemia, shortness of breath, fatigue, weakness, and then due to low platelets they’re at increased risk of bleeding.

The risk stratification that we have used traditionally for MDS is called the IPSS [International Prognostic Scoring System]. We have used this for the last 14 or 15 years. Now there is an updated version of this called the IPSS-R [Revised International Prognostic Scoring System], and the main components that we are looking for here are 5 different things. One is what we call the bone marrow blasts. The blasts are basically the pathologist identifying abnormal leukemia MDS cells in the marrow, and they give a percentage for those blasts. Anything above 5% is considered abnormal; the higher the blasts, more than 10%, more than 15%, the higher the risk associated for the bone marrow blasts.

The second factor we usually look at are what we call cytogenetics or chromosome analysis. There are certain cytogenetics that are favorable, certain that are intermediate, and certain that are adverse based on known outcomes in patients who have had these cytogenetic abnormalities. Based on that, we assign a score for cytogenetics.

The third and fourth things that we look at are anemia, the degree of anemia, and degree of transfusion requirement. Then the fifth thing that we often look at is the platelet count of the patient. Putting all these together, we come up with a score for that patient depending on what score was assigned for each of these variables, and that helps us know the IPSS-R for that patient.

There are basically 5 different categories in the IPSS-R: very low risk, low risk, intermediate risk, high risk, and then very high risk. Based on that, we know the expected prognosis, median survival and range for a given patient based on thousands of prior patients whose data were used to generate IPSS-R. More importantly, a lot of the therapies in myelodysplastic syndrome, especially the newer combination therapies, are more specifically geared toward the higher blast, higher-risk MDS, so we usually use this IPSS-R for that identification.

It’s also important to note that MDS is a precursor; there’s another condition called acute myeloid leukemia [AML]. The distinction between MDS and AML is usually based on blast percentage. Patients who have less than 20% blasts are considered to have myelodysplastic syndrome, and those who have 20% or more per the WHO [World Health Organization] are considered to have acute myeloid leukemia. Often this may be semantics as we can sometimes see patients with 16% to 18%, 19% blasts; if they’re young, fit and healthy, we may consider treating them as AML, and vice versa. However, in patients who have low-blast MDS, especially less than 5%, or 5% to 10%, there is often a biologically significant difference from those who have true AML. Usually looking at molecular mutation profiles, we can identify these differences. In a nutshell, this is how we identify MDS, what the blast cutoffs are for MDS, and what risk stratification and prognostic scoring systems are being used today for MDS prognosis.

In general, MDS is thought to be a spontaneously occurring disease with very few identified or known risk factors. We think that in about 85% to 90% of patients who develop MDS, this is due to the acquisition of genomic mutations over time with aging. Now, in the recent 10 to 15 years, a lot of work has been done, and we are identifying a few subsets of what we call familial, or genetic MDS. These are often patients who have mutations like 

, and may have cytopenias persistent for many years before the development of MDS. Also, heavy exposure to chemicals like benzene, radon, and arsenic, but usually this is very high exposure daily or multiple days a week over years that could put a patient at risk. This is a very uncommon with today’s environmental controls and checks, and we do not see this frequently as a cause of MDS. However, in the past, this was associated with MDS in a few patients.

Now, the big group of MDS that we are seeing more and more of is what we call secondary MDS. These are patients who have had another malignancy: colon cancer, breast cancer, lung cancer, brain tumor, and got chemotherapy and/or radiation for that prior cancer, and often had a remission and even sometimes were cured from that prior cancer. They may unfortunately develop MDS many years later, 4 to 8 to years later, due to the DNA damage from the prior cancer’s chemotherapy and radiation. This is what we call therapy-related MDS. Unfortunately, this type of therapy-related MDS often is associated with difficult and adverse cytogenetics and molecular mutations.

The good news is the incidence of therapy-related MDS is usually low, 1% or 2% of all cancers treated. Of course, we still need to treat the primary cancer because that would be the main cause of mortality, but it’s important to know that 1% or 2% of patients may develop a secondary or therapy-related MDS. For this group, we are now trying to design better or different treatments because this group of patients has historically been resistant to the traditional treatments that work in the de novo or spontaneous MDS.

The main complications of MDS are related to low blood counts. Due to low production of hemoglobin and anemia, patients are at risk for cardiovascular events such as strokes and heart attack. Low platelet counts make patients at risk of increased bleeding, and we do sometimes see patients presenting with MDS with bleeding from the gum, GI [gastrointestinal] tract, and in rare cases even severe intravascular bleeding. This could be in the brain or in the abdomen or other regions.

The most common complication is usually because of a low production of white cells or neutrophils; patients who have neutropenia are at high risk for infection. Probably the most frequent complication we do see with MDS is an increased risk of infection because of immunosuppression from low white cells.

Naval Daver, MD, explains myelodysplastic syndrome, including risk factors and potential complications.

Naval Daver, MD | Authors

Articles

The Future of Myelodysplastic Syndrome

Emerging First-Line Treatments for High-Risk Myelodysplastic Syndrome

Treating Patients with High-Risk Myelodysplastic Syndrome

Treatment Options for Low-Risk Myelodysplastic Syndrome

Diagnosis of Myelodysplastic Syndrome

An Overview of Myelodysplastic Syndrome