Improving Transplant Outcomes of Patients With MF

Tajuana Bradley

The best way to potentially cure or move patients with myelofibrosis into long-term remission is by an allogeneic stem cell transplant. In the community practice, we consider for transplant many of our younger patients and those patients who have high-risk disease. Transplants should be considered early on in the diagnosis for these patients. However, honestly, in our practice the majority of our patients are older, and they have multiple comorbidities that may preclude them from getting a transplant. Kristi, in addition to age and performance status, what are some of the other considerations we should be mindful of when we, from a community setting, are referring patients out to a practice like yours? What are you looking for? What do you consider to be an ideal transplant candidate?

Kristi Wiggins

The “ideal transplant candidate” is an interesting way to put it. I don't think there's any such thing as an ideal candidate. We want to look for somebody who is fit, and fitness for transplant means different things to different providers. There are varying degrees of opinions on who is fit for transplant. We know that folks who are referred into us usually have worsening blood counts, but moreover they have worsening of the symptoms that are related to the myelofibrosis. One of the points in the NCCN guidelines looks at starting therapy or changing therapy based on a patient's symptoms, not just the pathophysiology of the disease itself.

In our practice, we consider the age of the patient who’s newly referred but realize there is a difference between chronological age and physiologic age. Just because a patient is 70 years old, it doesn't preclude them from transplant, if they're a very fit, active, low-comorbidity 70-year-old. A 45-year-old patient may come in with multiple comorbidities, sedentary lifestyle, lack of psychosocial support, and few or no caregivers available. That patient would be a poor candidate for transplant. Having family or friend support is really important to consider when people come to transplant. I know the guidelines, I review the MPN10, a 10-symptom questionnaire that looks at age, performance status, and comorbidities. It addresses patient fatigue level, early satiety, and weight loss. We factor those items into our decision-making. We also look at what therapy they're on and if it’s working for them.

I think the biggest point we consider is patient preference. We lay out the options for a patient, including continuation of current therapy, considering other alternative therapies, or coming to transplant. Knowing there's a high mortality risk associated with allogeneic transplant, sometimes a patient will say, "I'm perfectly satisfied staying on therapy, and I don't want to take that risk right now." On the flip side, we have patients who walk into the clinic who are just tired of being tired. They're anemic, they have low platelets, which necessitates being in clinic every week for transfusion support. They are tired of living that way, so they're ready to take on the risk of allogeneic transplant. It’s a mutual, shared conversation with patients to discuss if they are ready for transplant, or if it's something they even want to consider. Tajuana, what do you consider when referring patients to a transplant center?

Tajuana Bradley

Often we try to get the patient referred for consideration of transplant early. We have various tools that we use to help us to prognosticate our patients and decide if they're low risk or high risk. And for the most part, many of our patients are eager, but not all of them are. Recently we had a patient who was in his mid-to-late 60s and very fit, but unfortunately, within two months after his transplant, he developed neutropenic fever and coagulopathies, and his post-transplant course didn't do well.

When you talk about the mortality from allogeneic transplants and then relaying this to patients,  sometimes we get resistance from the patients. Once a patient hears about the mortality rate associated with transplants, they may decide against transplant and just continue on with their current treatment. Another issue is the potential lack of marrow and stem cell donors. The patient I spoke of initially was going to use his son as his donor but ended up choosing his daughter who was a 5 out of 10 HLA allele match. As you know Kristi, HLA matching is used to match patients and donors for blood or marrow transplants. If 2 people share the same HLA type, they are considered a match.  Having a close match improves the chances for a successful transplant, helps donor cells engraft (grow and make new blood cells in your body), and reduces the risk of complications like graft-versus-host disease. While my patient had a haploidentical match with his daughter, unfortunately, he developed other complications and subsequently died. Another issue may be the donor source, and how we can help patients understand the process of donor sources.

Kristi Wiggins

You bring up a really great point. MF is a complicated disease with complicated side effects, and often, complicated therapy.  When adding these factors to the possibility of facing a stem cell transplant, patients can be overwhelmed. Add all of this to getting them to understand they need a stem cell donor, cells from another person, because their own cells are not sufficient to fight the disease with therapy alone. They need donor cells, a donor immune system, to replant that marrow to give them a healthy marrow again and hopefully protect them from this disease for the rest of their life. That is, if they survive the transplant therapy. We have to help families understand the need to do HLA typing of any siblings, knowing that a matched related donor is the most preferable type of donor. Having a matched sibling confers less risk to the recipient, reducing the risk of graft-versus-host-disease and rejection and providing better engraftment.

One of the points we make with patients is that if they have a matched sibling, a perfectly matched HLA donor who is willing to donate cells for them, this is the best option. We can usually collect as many cells as we want from that individual to provide to the patient. One of the things that's unique about myelofibrosis compared to other malignancies is that myelofibrosis causes scar tissue in the marrow. So, you need to be able to have lots of seeds to replant the garden for someone who has marrow scarring, versus someone who has leukemia or lymphoma where you may not need as large a cell dose. Having someone who's willing and able to provide an ample cell dose for their loved one is a really nice luxury to have if they have a matched sibling.

Tajuana Bradley

And if the patient doesn’t have a family member who matches or can donate, there are other routes we can take.

Kristi Wiggins

Yes, there are. The other option for patients is a matched unrelated donor, someone who has applied to the national donor registry and is willing to donate cells to a complete stranger. Usually, we can request how many cells we want and the collection center will try to meet that goal if they can. Overseas centers sometimes have a cutoff on how many cells they'll collect, so we are not always able to obtain as many cells as we would like for a myelofibrosis patient. Sometimes we have patients who belong to an ethnic minority or have mixed heritage. This sometimes makes it difficult to find these individuals a donor on the registry. You would think in today's day and age we would have enough diversity on the registry, to have a donor option for everyone, but we don't.

So, we encourage family members and friends of the family to enter the registry. It would be a blessing to have more donors from minority backgrounds and/or mixed ethnicities to choose from. Again, in our current climate, we think having a matched sibling is ideal. Number one, they come from the same two parents and have similar DNA, which reduces their risk. Having an unrelated donor from the registry could mean an increased risk of graft-versus-host disease. If available, we opt for a male donor. If a male donor is not available, we will go with a female donor, preferably one who is young and has not had children. This can help reduce the risk of donor antibodies against the recipient.  If a female donor has had multiple children it increases the risk of graft-versus-host disease for the recipient.

One of the donor sources that we use at our center is cord blood. Pregnant women can choose to  donate cord blood at the time of their baby’s delivery. It’s frozen for future use and serves as a good source for many diagnoses that require stem cell transplant. The exception is myelofibrosis.  Since MF causes scarring in the marrow, it limits available tissue for stem cells to engraft, or replant.  We need a large cell dose to overcome this scarring. When you use cord blood, it is customary for two cord blood units to be used in an effort to increase the cell dose for an adult-sized patient. But a cord blood unit contains a finite number of cells. Once you give that product, that's all the recipient gets; there's no way to go back to that donor to procure additional cells if you need them. That’s one of the huge shortcomings of cord blood for MF. We know that the risk of graft failure would be quite large in someone getting a cord blood transplant for myelofibrosis. So, it's something that we typically don't do.

Tajuana Bradley

Have you heard of anything else on the market, anything up and coming?

Kristi Wiggins

Yes I have. A company called Gamida Cell has a product in clinical trials called Omidubicel^® an advanced cell therapy candidate that may change the face of how we treat myelofibrosis. This product is a nicotinamide-based (or NAM-based) expansion technology that enables donor cells to grow while maintaining functionality, and therefore may address some of the cell count issues we just discussed with cord blood. We may have better donor options for these patients if Omidubicel^® is approved for use by the FDA.

Regarding survival rates, we know the more fibrosis in marrow at the time of transplant, the more that engraftment becomes an issue. One of the hardest things to determine is what rate of engraftment to expect in this patient population. We have some people who have level 3+ fibrosis on their marrow and engraft well. On the other hand, we have patients with 2-3+ fibrosis and don't engraft well. It’s a chance we take. But we know that the higher the fibrotic view of the marrow, the harder it is to get a really good, solid engraftment in those patients. And that's why a large cell dose is really important.

I want to go back a little to discuss donor cells, Tajuana. In your practice, have you had issues with getting siblings to have their HLA typing done for family members?

Tajuana Bradley

We have, and I think part of it is just lack of understanding and education, not having an awareness of the process. Unlike organ donation, for instance with donating kidneys and so forth, stem cell donation is just a quick blood draw. But we've had people who haven’t been willing to even get on the registry or get tested, and it's really unfortunate and sad because this can be lifesaving.

Kristi Wiggins

Right, I think some people don't realize that we all have stem cells. There are still some misconceptions out there that we are doing something experimental with embryonic stem cells. This couldn't be further from the case. We all have stem cells, and once they're removed, whether through peripheral blood collection or a marrow harvest, our bodies replenish those stem cells as soon as they are removed. So, it's a replenishable resource that we can give to people freely. It's not like giving an organ. If you give away a kidney or a lung, you won't regrow those, but you do regrow your stem cells.

I really think there is ample opportunity for us to do some education, getting the public to understand what stem cell therapy really is. People need to understand that it is safe, effective, and can save lives. It's a lifesaving therapy given without the donor losing anything. It doesn't impair the immune system. There are practically no long-term complications from being a donor.

However, there are differences in collection procedures depending on whether it is bone marrow or peripheral stem cells. Bone marrow harvest requires a surgical procedure to extract the stem cells from the marrow of the hip, specifically the iliac crest. It is usually a 1-hour day surgery. The main side effects are hip pain and fatigue. A peripheral blood stem cell collection requires growth factor injections to stimulate the bone marrow to grow lots of stem cells so they can be collected by IV from the peripheral bloodstream. The growth factor is given for five days and can cause bone achiness in some people. The collection occurs on the fifth day of injections and takes about 6 hours on an apheresis machine. The process is similar to dialysis. The stem cells are removed, but the rest of the blood is reinfused back into the body. Most donors experience fatigue after the collection is completed. There's a lot of work for all of us to do to educate our families and our patients when it comes to stem cell donation.

As we mentioned before, some patients are not candidates based on their comorbidities. There are many therapies on the market now that we didn't have 5-10 years ago, ruxolitinib being one of them, fedratinib being another. If someone is not a transplant candidate but their platelets are over 50, the NCCN guidelines recommend continuing treatment with ruxolitinib or fedratinib indefinitely, and monitoring disease response over time. One method of monitoring responses is to use the MPN10 or other standardized tool concerning symptoms to evaluate response to treatment.

Interestingly, the NCCN guidelines also say that if a patient is not a candidate for transplant but their platelets are < 50, they can consider a clinical trial or consider treatment with pacritinib. Pacritinib is one of the JAK-inhibitor medications that has less of an impact on the blood counts. It’s interesting that the NCCN guidelines say to offer it in patients with < 50 platelets and not those patients with platelets over 50. I think this will change soon. The future of MF treatment is going to include the mixing and matching of many available medicines to see what works for patients. I’m interested to see how the guidelines change based on these newer medicines coming onto the scene.

Tajuana Bradley

From our standpoint in a community practice, splenomegaly has a huge impact on how patients are feeling symptom-wise. A few studies have shown that a larger spleen size may be associated with inferior outcomes after transplant, possibly reflecting that the patient has an aggressive disease biology. We typically do imaging at initial diagnosis and then assess on physical exam at each visit. Kristi in your experience, from a transplanter perspective, are you all concerned about spleen size in MF patients? Does your team consider spleen size at all when you're evaluating patients and following them?

Kristi Wiggins

Sometimes. And, that's the honest truth. We tend to put less emphasis on spleen size than we do on molecular testing, genetic abnormalities, and how the patient may have deteriorated in their quality of life (QOL), including psychosocial issues. We also consider the patient's decision to come to transplant. The spleen is measured radiologically, recorded, and monitored. We often continue to measure clinically, but it's not high on the list for deciding transplant candidacy. Ideally, we would like to see a reduced spleen size prior to transplant. We typically keep patients on ruxolitinib or pacritinib to maintain QOL and spleen size control leading up to a transplant.

However,  we know that splenomegaly does play a role in overall survival. The larger the spleen, the lower the overall survival rates. In general, taking all comers, all ages, survival rates at five years after transplant are anywhere from 30% to 65%. That’s a huge range, depending on how you slice the different versions of myelofibrosis ages and donor types in these individuals. But survival rates continue to improve. I'm hoping now that we've added maintenance therapy, survival rates will improve even more.

One of the newer things that we've adopted from the myeloma world is looking at post-transplant maintenance therapy. After blood counts have recovered post-transplant, we often resume the agent they were taking prior to transplant. Sometimes they continue this for a couple of years. The theory behind that is, number one, it keeps the spleen under control because you have that extra medullary site that becomes active when the myelofibrosis is present. Secondly, this time or treatment allows the allogeneic donor cell engraftment to become stronger, to have enough strength to overpower the myelofibrosis. Ideally, in 1-2 years, the donor stem cells are strong enough to independently keep the myelofibrosis under control, hopefully for the rest of the patient's life.

The verdict is still out on how long we should treat people after transplant with some of these medications. It’s interesting that we're able to do that now without really harming the blood counts very much. Hopefully by remaining on these medicines, we can keep the splenomegaly at bay and eventually eradicate it, once they are fully engrafted and the donor cells take over.

Tajuana Bradley

Kristi, can you speak for a moment about the difference between peripheral blood and marrow for transplant?

Kristi Wiggins

Of course! We use peripheral blood cell stem cells collection as well as marrow harvest stem cells in myelofibrosis patients. Different providers will choose one type of product over the other for different reasons. We know that with marrow there is a slight reduction in graft-versus-host occurrence in those patients. The only problem with marrow is you really don't know how many cells you have until that marrow harvest is done, despite often doing a cell count check during the harvest procedure. A harvest is considered a surgical procedure. You're putting the donor through a surgery, and you don’t really know how many cells you have harvested until just before the cells are infused into the patient.

Granted, if it's a family member, you can request additional peripheral blood cells in the future if the patient needs them. We can also approach the donor for a collection of donor lymphocytes to help boost the patient’s immunity and boost the engraftment of the marrow. In our practice, we most often use peripheral blood cells. When the donor is on the apheresis machine you are able to count how many cells they have. Depending on the collection numbers, the donor can return for apheresis two or three days in a row if needed to collect enough cells. So, we tend to do more peripheral blood than marrow for myelofibrosis patients.

Tajuana Bradley

There’s so much to discuss with this topic.

Kristi Wiggins

There really is. One thing that is not often discussed is the need for a caregiver during transplant and recovery. Some institutions may be okay with patients having hired caregivers. We do not allow that. These individuals may have no idea what they're getting into. They aren’t as committed to the patient. They don't love the patient the way a family member or a friend would, so we prefer patients have friends or family as caregivers. Patients have much better outcomes, higher survival rates, with transplant if they have a dedicated family or friend caregiver, or multiple caregivers who they know and will support them through this. Having someone with the patient 24/7 for three months is a huge responsibility and commitment.

During the time of recovery, this caregiver does not have to be the same person. We want patients to have an appointed primary caregiver, as well as a backup caregiver, a backup plan, since life happens. Caregivers can experience their own health-care crisis during this time. If the caregiver needs to have their appendix removed in the middle of the transplant patient’s recovery, we want someone to be available as a backup.

Tajuana Bradley

It’s so important to educate patients on the importance of caregiving in the recovery process.