Improving Diagnosis and Care for Rare Cancers and Blood Diseases

Dale Shepard, MD, PhD:

Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist and co-director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Sudipto Mukherjee, director of the Rare Cancers and Blood Diseases Program at Cleveland Clinic. He was previously guest on this podcast to discuss management of rare cancers, and that episode is still available for you to listen to. He's here today to talk about the Rare Cancer and Blood Diseases Program. So welcome back.

Sudipto Mukherjee, MD, PhD, MPH:

Thank you, Dale.

Dale Shepard, MD, PhD:

So, remind us again what all you do here at Cleveland Clinic.

Sudipto Mukherjee, MD, PhD, MPH:

Going back to our last podcast, which was in 2021, just to give a brief background, currently I direct the Rare Cancers and Blood Disease Program, which was actually an initiative back in 2015, 2017, and in 2019 got formalized as a program once we had enough patient volumes. So the Rare Cancer and Blood Diseases Program is actually not a freestanding program per se, that is not what we'll see it as. It is actually a multidisciplinary program, extends across the entire enterprise involving multiple other specialties, cardiology, pulmonology, rheumatology, etcetera. And what it does is it has the clinical and the surgical expertise and pathologic expertise and knowledge about diagnosing and managing a whole bunch of very ultra-rare cancers and conditions, which was over the years we started with about 70, then it went up to 84, and now we are seeing almost slightly over 90 rare cancers and blood conditions.

And for each of these rare cancers and blood conditions, we actually have a multidisciplinary team, meaning for any particular cancer, you may have a dedicated person or a champion, for example, from hematology, depending upon the organ involvement with that rare disease in that patient, we may have a dedicated person from cardiology, neurology, from nephrology, so basically we can provide a multidisciplinary integrated approach. And what really aids in this process is we even have dedicated pathologists for these rare diseases, and it has been a very phenomenal journey and a very impressive growth in this program over this past seven, eight years.

Dale Shepard, MD, PhD:

So, I'm going to take a really quick step back. When we talk about rare cancers, you mentioned ultra-rare cancers, how are we defining that?

Sudipto Mukherjee, MD, PhD, MPH:

That is actually a very interesting question, and I get asked about that a lot. And I think it's a little bit tricky because if we were to go by the rare cancers' definition that is usually used by international organizations and including the National Institute of Health, those numbers will fall somewhere around 3.5 to five cases per hundred thousand per year. We have to understand that cancer itself is kind of rare when you compare it with cardiovascular disease or chronic kidney disease or diabetes, so having rare cancers would seem like an oxymoron because all the cancers are rare. So we deliberately decided to apply a very restrictive, rigorous criteria, where we define rare as less than two cases per hundred thousand per year. So really you're looking at exceedingly rare conditions, and this actually gives it a little bit of clarity as to how do we stand separate from the much more liberal nomenclature that is used in outside cancer centers and institutions.

Dale Shepard, MD, PhD:

And it seems like even what would on the surface be a common cancer is now becoming a series of rare cancers. We used to be really brain and lung cancer and we'd have non-small cell and small cell, and now you sort of work your way down and you have very, very specific subsets.

Sudipto Mukherjee, MD, PhD, MPH:

Absolutely. I mean, now we know, especially with all these genomic designations of cancers, these have their own particular niche, own particular targeted therapies, so very much to the point in lung cancer, I think even in sarcoma, even in GU cancers now, not all prostate cancers are the same or not all urological cancers are the same. So as we learn more about these genomic advances and we apply them, we are seeing that within a big giant umbrella of a cancer type, there are certain very well-defined genomic entities which by themselves may be classified as rare, and we do acknowledge that.

Dale Shepard, MD, PhD:

When you look at the growth and as things have gone from, you said around 70 to over 90, are there particular types of cancers that are more represented more, are there more hematologic malignancies, more solid tumors, what does that mix look like?

Sudipto Mukherjee, MD, PhD, MPH:

The best way to answer that question is the mix of cancers that we see has changed over the years in the sense that for some cancers we actually have made quite a bit of progress in terms of research and publications. And as you know, for these cancers, when the word is out, people get to know about it, and particularly for those cancers, they show up. So our mix is not necessarily a mix based on their best estimated prevalence. It's also based on at any particular year, what have we achieved in any particular cancer because that attracts, that gets information out that gets more patients in. So I would say the way we look at it is more common among the rare. And what I mean by that is among all these rare ones, which are the ones where we had seen really an explosive growth in volume, and they tend to be a little bit more hematologic, rare conditions or malignancies heavy compared to the solid tumors.

But as you know, directing the sarcoma program, obviously the sarcoma program is a very successful, you get a lot of patients. Similarly, for certain genomic subsets of lung cancers, we are seeing an increase in the number of those cases, ALK-positive cases have really shown an increase. On the heme side, we have really seen a very huge growth in Castleman disease and all its variants, we have seen big growth in all kinds of histiocytic disorders. We are seeing a big increase in mast cell disorders, particularly systemic mastocytosis, and we have started to see a trickle of cases starting to come in and we are seeing more cases and we may have more numbers by the time next year rolls by, and that is because we included them now in our rare disease conditions and they are particularly littoral cell angiomas, we also started recently seeing kaposiform lymphangiomatosis, and we used to see a lot of these rare cases, but it was never integrated in the rare disease program, but now we have formalized it and we expect to see an increasing volume of acute porphyrias and lysosomal storage diseases.

So this is the difference from three or four years ago. As we expand the number of diseases, as we do more work about them and publish research, we get more for those conditions and the mix keeps on changing year to year.

Dale Shepard, MD, PhD:

So, on that research question, so there's certainly power in having a program that can just help people understand their disease, make sure they have an accurate diagnosis. Oftentimes I realize they come in and their doc may or may not have ever seen a case, and so there's a lot of importance just to that part, but what are you seeing from the standpoint of research toward treatment for some of these rare diseases? Historically, companies would flock to things that were high prevalence because that's where the patients are. Are you seeing that there's more and more interest in attacking some of these rare diseases?

Sudipto Mukherjee, MD, PhD, MPH:

There is, and lately so, it was not the case before, but in the last three, four years, we have seen a really concerted effort by a number of pharmaceutical companies, and that is because there is a slow realization that there's a significant large unmet need. And these patients are such where the focus for developing new therapies actually comes into play from a pharmaceutical industry standpoint is, if it is going to be an economically viable option for them. And it is turning out to be an economically viable option for them because if you have identified molecular targets, then these patients are going to be on these therapies indefinitely for the rest of their lives unless they have a disease progression or unacceptable toxicities. And one case in point is for the Castleman disease that we use siltuximab an IL-6 monoclonal antibody, they get that IV infusion every three weeks for the rest of their lives.

And we have several patients now who have been on these therapies at least four or five years, and amazingly they continue to carry on with their day-to-day lives. So there's something to be said about a therapy that is lifelong. So they're not dying of this treatment, dying of these diseases anymore, they're living with these diseases with the treatment. That's number one. Number two is we are slowly seeing a lot of crosstalk in the biology of these different rare diseases. So you may have a single genomic mutation can be the target for intervention for a wide variety of diseases. And one of the examples I will give you is, and we have started actually using that, is for the longest time the JAK inhibitors were the cornerstone of therapy for myeloproliferative neoplasms, and now based on some of the research that we have participated in, the JAK-STAT pathway is also very active in Castleman disease.

So now what we are trying to do, and with some success, is in patients with Castleman disease who have been on cetuximab and either intolerant or resistant, our next line of treatment has become JAK inhibitors, which are oral pills, so much more easier and convenient for the patients, and we have been able to salvage some of these cetuximab refractory patients. So a repurposing of the drugs is what I'm getting. And these kind of stories are coming across in other diseases too. And another good example is we now have identified in the histiocytic disorders, there's one particular entity now that is defined solely by the presence of ALK mutation. So we have a new entity called ALK histiocytosis, and clearly they respond very well to ALK inhibitors and something that we actually borrowed from the lung cancer field. So it is very fascinating that we are seeing all these cross drop in the downstream signaling of varied diseases, which gives us hope that maybe there's a lot of potential for repurposing the drugs.

Dale Shepard, MD, PhD:

Yeah. I mean, you mentioned targets. I mean, that's important. If you get a large number of people together, you might be able to identify those targets. I mean, just thinking in my world, tenosynovial giant cell tumor, there's not very many of them, but because we have a target now, there's two approved drugs, one's up for approval, two more in development. I mean, it becomes something where everyone sort of starts to focus on, so that helps. How do you work with other institutions that have rare disease programs and help either from a research standpoint or clinical practices or what does that look like?

Sudipto Mukherjee, MD, PhD, MPH:

Usually it starts at the very beginning with whenever the Cancer Answer gets a call from anybody outside, we used to rely on initially getting the reports and the slides before we would assign somebody to see those patients. But as you are very well aware of, the slides and the reports never ever reach on time and that causes unnecessary delays and anxiety for the patient, and one of the biggest selling points is access. So what we decided, this is a couple of years ago, what we decided was if anybody calls us with having told that they have a rare condition or they're doubting a rare condition or they may have something, we will try to get them in, irrespective of whether by the time they reach here, they have the records or not, because we have realized that just even talking to them makes them feel very informed, makes them feel very knowledgeable about what they possibly could have, and they have a game plan.

They have a plan of what comes in next, how are we going to address this? So when these kind of calls comes to Cancer Answer scheduling department, we actually have trained a few of them and they have become extremely good at it. They look at those diseases, they get the best information they can from whatever is available, and then they triage those patients. I would sit down with them and then depending upon, for some patients who we have a known diagnosis and known organ involvement, we would send out an email to contact those respective physicians or champions in other institutes like, "Hey, the patient is coming here on this and this day. How about all of us try to at least get all investigations done and a visit completed in a day or two?" And that is huge because sometimes I feel it blows my mind because rarely for an organization this big to make all that work and be in sync and get everything done in a day or two is unbelievable because there's so many moving parts to this.

And for the patient, I think it is an unbelievable experience because after going around for three or four years doctor shopping and trying to figure out what it is, they come here and then within two days they have seen everybody that they needed to see and they walk out. Even if they don't have a confirmed diagnosis, they feel extremely comforted and confident that in the next couple of weeks we will have a diagnosis, we will either confirm or rule it out. And this approach and the fact that we promise very quick access, so especially right now we say anybody who calls in, they will be seen within five business days, period. If they can make it here, we'll see them within five business days. And that is going to change drastically too, because starting next year, we are trying out another plan where we are going to shorten the duration.

So anybody who calls in with rare diseases, our promise would be to see them within 48 hours of contacting us in business days. It has also worked out for the other specialties too, because now we have a group of physicians scattered all over the enterprise who enjoy seeing these patients, it has definitely improved their clinical expertise and it is giving them opportunities for them and for us to collaborate and do research. So I think it's a massive win-win for the patients, but it is also helping the clinicians and we are learning and developing our expertise and it was a steep learning curve, but we are at a point where we are reaping the dividends from having invested in this a few years ago.

Dale Shepard, MD, PhD:

Fantastic. So a couple follow-ups from that. First, the diagnosis piece. So certainly it probably varies widely based on what that disease might be, but somebody comes from another institution, they've been told they have something. On average, how often do we confirm that diagnosis and how often do we have a change in plan based on our interpretation of pathology?

Sudipto Mukherjee, MD, PhD, MPH:

This actually is one of the big facets of the program. The program exists not just because we have to give you a diagnosis. Another objective of the program is to make sure if you don't have it, then you should not be given that diagnosis and live with it for the rest of your life. And give or take on an average across all these entities, we will confirm or change the diagnosis. We'll confirm the diagnosis in slightly over 50% of the cases we'll agree with the outside report. We always make it a point to get the biopsy slides and review and stain and do the gene analysis before we confirm those reports. In 20% we will change the diagnosis, so it might be within the same disease category, but it might be a little bit of a different flavor. In 20%, we flat out overturn the diagnosis. They don't have it.

And it is a huge relief for the patient because they then don't have to live with the stigma of the disease that they never had in the first place. And pathology is, as you are very well aware from your experience in sarcoma, that pathology is critical. If the pathology is not well reported, it can lead you down a rabbit's hole. It can be a source of huge frustration and anxiety.

Dale Shepard, MD, PhD:

I mean, from your previous example, missing an ALK-positive tumor would be huge.

Sudipto Mukherjee, MD, PhD, MPH:

Yeah, the implication would be huge. I mean, a condition that could be treatable, maybe not curable, but treatable, and getting the patient a good few years of good quality life.

Dale Shepard, MD, PhD:

I guess the other thing is a follow-up would be about collaboration with other providers. So you can't run a rare disease program simply in Northeast Ohio, you're no doubt getting people from a distance. How do you best collaborate with the providers back home to make sure the right things are being done in terms of follow-up imaging or treatments, things like that?

Sudipto Mukherjee, MD, PhD, MPH:

There's no best way to answer that question, and there's no best approach. So usually what happens is we have employed a couple of different approaches. One of them is the clinic second opinion option, which where a lot of these consults come through, so that is one source of developing our footprint further wide. Why I say that is this is usually a review of the records and giving your recommendation, but then we have seen more than 50% of them actually turn out to be a follow-up visit here at the main campus. Knowing and being fully cognizant of the fact that all the rare cancers are not going to be in and around Northeast Ohio, in fact, we are trying to spread our footprint both nationally and globally, and the way we do it is once the patients are here and we develop a treatment plan and then they go back to wherever they came from, we then have a shared care approach.

So these patients, they will have two levels of providers involved, one locally, one here, and they will follow for the most part locally, but they will come down here once or twice a year to get all the necessary imaging done, because we want to make sure that all those are done in the same place. So we compare apples to apples and oranges to oranges. And second of all, sometimes because of the delays in getting the CDs from outside places, we better want to keep everything in one place. We have also collaborated with other national and international organizations for rare diseases, for example, the North American Histiocytosis Organization and the Castleman Disease Collaborative Network where you have a whole bunch of institutions nationally and internationally who are part of the consortium, so we are listed in those places as centers of excellence.

So if any institution, say for example, University of Arizona has a patient who is moving here or wants a second opinion and they have a family member here, so they can just go to that website and say, "Okay, we have Cleveland Clinic Care, we have this doc here. Since you'll be going there, why don't you just go and see the physician over there?" So many different ways we are trying to, so basically through social media, through patient advocacy groups, through our second opinion through the clinic, having multiple licenses in different states that allows us to get the privilege to do virtual visits and continue to be involved in the patient care along with their local doc, and through these international rare disease consortiums. So it's a multipronged approach. It seems to be working well.

And finally, what we have been able to achieve is a very rare distinction that we are, if not the only one, we are just a handful of cancer institutes across the entire country who has this very rare distinction of having the Center of Excellence designation from NORD, National Organization of Rare Diseases, which has tremendously helped us in spreading news about the work that we do and getting people here.

Dale Shepard, MD, PhD:

Fantastic. It's been a long labor of making this all work out and getting all the parts and pieces together, but you're doing great things.

Sudipto Mukherjee, MD, PhD, MPH:

I would be amiss to not mention that in the initial formative years, you were an accomplice in this effort.

Dale Shepard, MD, PhD:

I was indeed, and I was happy to do it, and I'm proud of what you put together. Well done.

Sudipto Mukherjee, MD, PhD, MPH:

Thanks, Dale.

Dale Shepard, MD, PhD:

All right. Well, thanks for joining us with your insights, and we'll try to make it a little quicker to get you back for some more updates.

Sudipto Mukherjee, MD, PhD, MPH:

Thank you.

Dale Shepard, MD, PhD:

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