Dr. Heather Landau is an oncologist and hematologist at the Memorial Sloan Kettering Cancer Center, bone marrow transplant specialist, and director of their Amyloid Program. In this video Dr. Landau reviews the history and goal of treatment for AL amyloidosis. Next she delves into detail and experiences of using high dose therapy and autologous stem cell transplant to treat light chain (AL) amyloidosis. In conclusion, she will discuss how the treatment landscape has changed based on recent advances.
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Rebuilding the Immune System
Losing one’s immune system is a serious consequence of a stem cell transplant, putting the body at risk for viral, fungal, and bacterial infections. Rebuilding the body’s immune system is a key part of the recovery.
LOSING ONE’S IMMUNE SYSTEM FROM A STEM CELL TRANSPLANT
A stem cell transplant (SCT), whether autologous or allogeneic, begins with chemotherapy, which is intended to eradicate problematic cells. Especially when administered in high doses, chemotherapy damages the bone marrow, leaving it unable to produce enough red blood cells, white blood cells, and platelets for a period of time – hence the reason for the re-infusion (or transplant) of stem cells. Following the transplant, the body begins to re-establish its cell production.
This killing of white blood cells severely compromises the body’s immune system, making the body vulnerable to even the tamest of infections and diseases for a period of time. And while infection remains the leading cause of post-transplant complications, protection against vaccine-preventable infections also a priority. Rebuilding the immune system is, therefore, paramount to recovery.
REBUILDING THE IMMUNE SYSTEM
Rebuilding the body’s immune system happens in two ways:
1) Immune Reconstitution. After the transplant, the body begins to naturally rebuild its immune system. White blood cells typically take between 21 to 28 days to return to a near-normal level, with B- and T-cell recovery taking approximately one to three months post-transplant. Healthcare providers will closely monitor this, as the trajectory of recovery can vary from patient to patient. For example, according to the Fred Hutchinson Cancer Research Center, after chemotherapy, the immune system recovery can be slower than believed, in some cases upwards of nine months, particularly in smokers.
2) Revaccination. Vaccination is an important process used to prevent many infections and reinstate, prolong, and/or extend immunity. The process typically begins one-year post-SCT and spans approximately twelve months.
CARE DURING THE REBUILDING PERIOD
During the recovery process, it is important that patients and those in frequent contact are more cautious. Some things to consider include:
- Get minor symptoms checked out, as they could turn into something more serious
- Get revaccinated
- Avoid disease “hot spots”
- Stay active and eat well
- If a smoker, try to quit
REVACCINATION PROCESS
The topic of revaccinating SCT patients isn’t entirely straightforward. Repeat vaccinations or boosters are often crucial in reinstating, prolonging, and/or extending immunity. Patients can be tested beforehand to find out which vaccines are needed and which ones are not required due to adequate antibody levels in the blood. This is determined through a simple blood test known as a titer. Vaccines would then only be given if the titers show a lowered or absent level of protective antibodies for the disease.
Distinguishing live virus vaccines from inactivated vaccines is taken into consideration when planning the revaccination process. Patients who are immunosuppressed, including post-transplant patients, should wait at least 24 months post-SCT and until they are no longer receiving immunosuppression, free from graft-versus-host disease (GVHD), and have immunologic response before receiving live vaccines. Live virus vaccines use the weakened (attenuated) form of the virus. Inactivated vaccines are made from the killed version of the germ that causes a disease. Live virus vaccines are used to protect against:
- Measles, mumps, rubella (MMR combined vaccine)
- Live attenuated influenza vaccine
- Oral (Sabine) polio
- Rotavirus
- Smallpox
- Yellow fever
- Typhoid
- Chickenpox/Shingles (Varicella)
The typical timeline begins one-year post-SCT and extends for 12 months. It may be adjusted by healthcare professionals due to patient-specific factors such as pregnancy or active graft-versus-host disease (GVHD). Vaccinations are typically given at the following timepoints:
- 12 months post-SCT
- 14 months post-SCT
- 16 months post-SCT
- 24 months post-SCT
It is important to be aware that SCT recipients may remain immunocompromised far beyond two years post-transplant, especially individuals with chronic GVHD. Therefore, transplant patients should have their titers monitored and be appropriately revaccinated until they regain immune competence.
“HOT SPOTS” TO AVOID
Time is required to rebuild an immune system – on average two years post-SCT. This necessitates that patients be mindful of what they could be exposed to in regions that they are considering visiting. “Hot spots,” or locations which exhibit an above-normal level of disease existence, are particularly problematic to those with a compromised immune system. According to the Center for Disease Control (CDC), many developing and emerging countries demonstrate a notable level of outbreak of diseases including yellow fever, typhoid, mumps, and measles. Having said that, diseases can transcend boundaries due in part to the ease of global mobility. Per the CDC, several northeastern states in the U.S. have a high level of reported mumps cases, and mumps remains a common disease in areas such as Europe, Asia, the Pacific, and Africa. Interestingly, according to a recent study published by the Public Library of Science, a number of American states and metropolitan areas are vulnerable to become a “hot spot” with an outbreak of a vaccine-preventable disease from children whose parents opted out of vaccination. Being aware of such “hot spots,” both domestically and abroad, is important.
CONCLUDING THOUGHTS
Healthcare professionals skilled in administering different types of chemotherapies and stem cell transplants are key to monitoring and guiding patients through the rebuilding of their immune system. They will provide details with regards to the timeline and process for revaccination, ensuring patient-specific considerations are incorporated. It is important, though, for patients to understand the rebuilding of their immune system is a process that typically spans two years, during which they should maintain an appropriate level of awareness and caution.
Sources: Journal of the Advanced Practitioner in Oncology, Fred Hutchinson Cancer Research Center, Be The Match, MD Anderson Cancer Center, CNN, CIBMTR, American Society of Hematology, Center for Disease Control, Public Library of Science (PLOS).
Transplant: Inpatient vs Outpatient
There is no cure for Amyloidosis.
There are, however, an increasing number of treatment alternatives that can significantly reduce, if not eliminate, the disease and put the patient into remission. The most aggressive treatment is a stem cell transplant (SCT); sometimes referred to as a bone marrow transplant.
Stem cells are cells in the bone marrow from which all blood cells develop. This treatment aims to eradicate, typically through high-dose chemotherapy (e.g., melphalan), the faulty plasma cells which make the amyloid light chains. Once eradicated, fresh cells, harvested from the patient themselves (autologous), a donor (allogeneic), or an identical twin (syngeneic), are infused into the patient. This will help to recreate a healthy bone marrow and hopefully stop further production of the amyloid protein.
This complex treatment typically takes four to six weeks and is performed on an inpatient, outpatient, or some combination, depending on the hospital. There are meaningful differences that are important to know and incorporate into each patient’s personal situation in order to make an informed decision.
From the Healthcare Perspective
Across the country, there are multiple hospitals that perform SCTs to treat amyloidosis. While hard data is elusive, the tally of transplants at each facility, we know, is not spread evenly. We do know that Mayo Clinic (Mayo) and Boston University (BU) dominate the list and perform the majority of transplants. It may not be a surprise, then, that these two hospitals are considered amyloidosis Centers of Excellence in the U.S. They see a high volume of cases, have extensive depth and breadth of expertise, and have sophisticated diagnostic equipment. They are also the two hospitals who have pioneered performing outpatient transplants. The good news is this is evolving, with more centers across the country expanding their transplant program to treat amyloidosis.
Everyone would agree that hospitals are germ and bacteria magnets, which can be dangerous for transplant patients with low to no immune systems. BU and Mayo, for example, found patients were better able to withstand the everyday germs outside of the hospital better than the more potent ones within hospitals. This provides a strong incentive for hospitals to consider outpatient, or if they choose the inpatient route, must be ever super mindful of this reality.
There are risks with SCT, and patient safety is key. Having a patient in-house during the treatment affords the hospital maximum control during the process, while being outpatient transfers some responsibility to the caregiver, such as monitoring the patient’s temperature, food, and fluid intake. Being inpatient also affords the quickest access to experts, equipment, and drugs in the event things go awry, which does happen. Mayo has found that a meaningful percentage (38% according to Dr. Morie Gertz) of patients never need hospitalization during the SCT process; however, on the occasions where it is necessary the duration averages a handful of days.
Treating patients on an outpatient basis requires hospitals to alter their process and training, and rely on the patient and caregiver to assume a more engaged role. Without question, hospitals benefit significantly from the experience of performing high volumes of outpatient transplants. Mayo, according to Dr. Morie Gertz, performed their first SCT in March 1996, and their first outpatient SCT in September 1998. In total, they have performed 744 SCTs and currently average about 33 transplants per year. According to Dr. Vaishali Sanchorawala, BU performed their first SCT in July 1994, and their first outpatient SCT in October 1996. In total, they have performed roughly 675 SCTs for AL Amyloidosis, with an annual run rate ranging between 25 and 50. Together, these institutions have over two decades of valuable experience. According to experts, small volume and the resultant lack of experience is likely the key driver behind why hospitals elect to perform SCTs on an inpatient basis.
From the Caregiver Perspective
Caregivers play a critical role in the SCT process, working closely with the healthcare team to ensure the patient is progressing appropriately. They are so critical, in fact, that regardless of inpatient or outpatient, hospitals will not proceed with a SCT unless they are confident the patient has capable and continuous caregiver support.
The role of a caregiver varies greatly between an inpatient and outpatient process. When inpatient, the caregiver provides important emotional support, as being confined to a hospital for weeks on end can be draining and discouraging. This can range from just being present, to chatting, to light activities. Caregivers also assist in the physical need for exercise, helping and encouraging the patient to walk whenever and however many steps possible. The caregiver role may be filled by one or more persons, often impacted by the distance the hospital is from home.
Outpatient SCT procedures are significantly more demanding of caregivers. For the duration of treatment, the hospital will require the patient and caregiver(s) to be proximal to the hospital. Mayo, for example, requires patients to be within ten minutes of the hospital. Fortunately, there are many hotels, motels, inns, and homes for rent (HomeAway, VRBO) that are transplant-friendly and reasonably priced. It is 24/7 support, monitoring the patient’s key indicators, administering and monitoring meds, transporting the patient to/from the hospital daily, securing meds, shopping and preparing food, maintaining the household (e.g., laundry, sanitizing, etc.), and on and on. The list is extensive and exhaustive. Arranging for such intensive support can be a challenge. Some patients assemble a series of caregivers who rotate in/out for periods of time, others are able to secure one dedicated caregiver for the entire time, and in rare instances, the patient is able to have a team of caregivers for the duration.
Whichever caregiver structure is chosen, it is important to also consider self-care for the caregiver. Mini breaks can go a long way to help sustain their ability to meet the needs of the patient and the requirements set forth by the hospital.
From the Patient Perspective
For patients, it is all about getting through this treatment and hopefully arriving at a successful outcome. Time distills down to weeks, then days, and then when things are their most difficult, just getting through the next hour is the focus.
Having a good and capable caregiver(s) in place can help the patient focus only on themselves, knowing the caregiver will take care of everything else.
Side effects of the SCT can be multiple and vary from patient to patient. The list of effects can include fatigue, fever, diarrhea, nausea/vomiting, loss of appetite, mucositis, and hair loss. Fortunately, the healthcare team can be very helpful in mitigating these effects.
Exercise is important to ward off muscular atrophy and does improve recovery. Every step matters. Both Mayo and BU find patients do better and are home quicker if they spend less time in bed and more time moving around. In addition, patients tend to benefit from the required additional movement needed when living away from the hospital.
Emotionally, a SCT is tough. No way around that. But having distractions, whether provided by the caregiver, getting out of bed to exercise or being out and about via outpatient does contribute to an improved psyche. Having any sense of normalcy is welcome.
Cost differs greatly between inpatient and outpatient treatment, with outpatient coming in meaningfully less expensive. Anecdotal information has outpatient transplants at roughly 50% off the cost of inpatient transplants. Yet regardless of the approach, SCTs are extraordinarily expensive, and most likely patients need their insurance to sign off before treatment can begin. One of the considerations by insurance companies is which hospital the patient is proposing for treatment. During our personal experience, where we dealt with two national insurance companies, both informed us that having treatment at a Center of Excellence made a difference.
Finally, what is it really like? While situations vary widely from patient to patient, as may treatments and outcomes, hearing about a SCT straight from a patient who has been there is helpful. Having had an outpatient stem cell transplant in July 2017, hear Mackenzie’s perspective while fresh post-Mayo. Additionally, preparing for an outpatient SCT is more involved for the patient and caregiver; we have provided SCT and Post-Chemo Tips on the Resources page of our website which others may find helpful.
Closing Thoughts
There is strong evidence over many years and many transplants that patient outcomes are better when performed on an outpatient basis. There are, however, notable implications for the healthcare providers, patients and caregivers, depending on which approach is chosen. Inpatient, outpatient and hybrid approaches can provide successful outcomes, but knowing these differences in advance is helpful to the decision-making process.
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Special Thanks
Morie A Gertz, M.D., M.A.C.P.
Consultant | Division of Hematology | Roland Seidler Jr. Professor Department of Medicine | College of Medicine | Mayo Distinguished Clinician
Mayo Clinic
Vaishali Sanchorawala, M.D.
Professor of Medicine | Director, Autologous Stem Cell Transplant Program | Director, Amyloidosis Center
Boston Medical Center and Boston University School of Medicine
Fruit & Veggie Food Safety
Too lazy to wash your fruits and veggies? Here are a few statistics that may inspire you. The Centers for Disease Control and Prevention says about 48 million people are stricken with foodborne illness each year; 128,000 are hospitalized. Approximately 3,000 people die.
For patients with impaired or compromised immune systems, such as those going through chemo/stem cell transplant, practicing good food safety goes a long way.
Amyloidosis By The Numbers
As a member of the amyloidosis community, we consistently engage in conversations with patients across a variety of forums. One constant among these patients is a desire for more knowledge. We want to learn about symptoms, treatments, and how we are all impacted by this disease. To get some answers, Mackenzie’s Mission created a series of online questions. We heard from 575 respondents. Here are their answers. Disclaimer: we are simply reporting the data as submitted.
In response to what is your current age today, the range was between 20 and 89, with 92.6% falling between the age of 40 and 79, and 83% falling between the age of 50 and 79.
In response to what was your age at time of diagnosis, the range was between 10 and 89, with 91% falling between the age of 40 and 79, and 63.8% falling between the age of 50 and 69.
The gender of respondents was somewhat balanced, with 54.5% female and 45.5% male.
The respondents currently live in 25 countries/areas around the globe, with 82.09% from the United States.
The types of amyloidosis were also diverse, including Primary/AL, hATTR, ATTRwt, Localized, and Secondary/AA. About 3% of the respondents were types outside of these, or unknown.
When asked about the number of organs affected, the majority at 56.5% had two or more, followed by 36.7% with one organ involved. A small 6.8% had no organ involvement.
Next, we asked the respondents for specifics as to which organs had been affected by the disease. The heart and kidney were the most common, with the GI Tract and Nervous System coming in similarly at third and fourth. Fewer respondents listed problems with the liver, lungs, spleen and larynx. In addition, there was a surprisingly long list of other involvements filled in, each receiving just one tally.
The next four questions focused on the specialty of doctors that patients had visited, and the time to diagnosis. We first asked how many doctors each respondent saw before getting a diagnosis. It is interesting to see how evenly it is spread across the selections.
We then wanted to know where their journey began. What was the specialty of the first doctor the respondent visited? It was not a surprise that the majority of responses, at 53.9%, named their PCP/Internal Medicine as their first stop.
The next question was to determine what type of doctor made the amyloidosis diagnosis. The data seems to indicate that while PCP/Internal Medicine was the first point of inquiry at 53.9%, they arrived at a diagnosis only 1.9% of the time. Thus, referrals to specialists were key to getting a diagnosis, with nephrologists, hematologists/oncologists, and cardiologists the front runners at an aggregate of 72.9%. Having said that, per the earlier chart, it took many specialists to arrive at the answer.
Next, we wanted to know how long it took to get a diagnosis. We were surprised to learn that 50% of respondents said they received a diagnosis within the first six months, especially given the number of doctors visited to arrive at the diagnosis.
We then asked respondents to list all symptoms they experienced. The dominant symptoms were fatigue and shortness of breath – 64.2% and 53.7% respectively. The “Other” category came in strong at 22.4%, with an extremely long and diverse list of additional symptoms (too many to mention here). It does seem appropriate to observe that the diversity of symptoms reflects the complexity of this disease.
We wanted to better understand how long patients experienced symptoms before they sought medical attention (this is of course with the benefit of 20/20 hindsight). Some 37.6% of respondents sought treatment early, waiting six months or less. However, nearly half — approximately 46% — experienced symptoms anywhere from six months to three years before their first doctors visit.
We asked respondents the types of treatments they had undergone since diagnosis. A significant 77.8% had various types of drug therapy and 37% received a stem cell transplant. A number of the patients having a stem cell transplant also had drug therapies, so these responses are not exclusive of one another.
For those who underwent a stem cell transplant, we wanted to understand whether the procedure was done as an inpatient, an outpatient, or as a combination. The majority at 68.5%, for a variety of reasons, were inpatient.
Our next category of questions focused on clinical trials. Of our 575 respondents, roughly one-quarter have participated in a clinical trial.
We asked those who participated in a clinical trial which one they were in. You can see below the distribution for the ATTR trials. We did ask a separate question regarding the AL-focused trials, however the data proved to be questionable and thus it was excluded from this recap.
The next question was aimed at the 77% who indicated they did not participate in a clinical trial, seeking to understand why not. Striking was the number of respondents who declined, for whatever reason, to answer.
In the next question we asked respondents to provide some insight into how they rated their ability to tolerate treatment, whatever that may be. It was spread out, perhaps due to a wide range of treatments.
We then asked patients to assess their quality of life before and after treatment. For those that responded, the majority indicated at least a moderate improvement.
In our next-to-last question we asked the current state of their disease.
The final question was open-ended, where we asked respondents to complete the following sentence: “With hindsight, I would have appreciated knowing about …” We received a massive number of responses, and in our desire to give everyone their full and unedited voice, we invite you to read through the many heartfelt and authentic voices (listed in the order received). “With hindsight, I would have appreciated knowing about …”
CLOSING THOUGHTS
The responses we got from this study reinforce the complexity and diversity of amyloidosis. To each member of this community who stepped forward to answer the questions, we thank you. Gathering information, spreading awareness, and pushing for change leads us on the path to earlier diagnosis and an increase in life-saving research.
One repeating point people mentioned in the last question was a need for more information for doctors and members of the medical community, and for patients and caregivers who are dealing with this disease. If we continue to reach out to doctors, they will recognize the symptoms of amyloidosis and will think to test for it, leading to earlier diagnosis. If we continue to provide patients and caregivers with the most up to date information on treatments, resources, and where they can go for support, we can help arm those who are newly diagnosed. In this way, the sharing of information can be one of our most valuable tools.
Fight on, amyloidosis warriors. Fight on.
Building a Caregiver Team
BUILDING A CAREGIVER TEAM
There are times when those afflicted with amyloidosis need assistance — a caregiver. In some instances, such as a stem cell transplant (SCT), the treatment is so extensive that securing a caregiver is required before treatment commences. It is for these situations that we thought we’d share some thoughts about how to build a caregiver team.
CONSIDER YOUR NEEDS
The role of a caregiver can be intensive and draining. In particular, SCTs performed on an outpatient basis, while deemed to be good for patients, shift a significant amount of work to the caregiver (see https://mm713.org/transplant-inpatient-vs-outpatient/).
Begin by itemizing the different aspects surrounding your caregiver roles, such as the following:
- Expected duration of treatment
- Location
- Meals (e.g., cooking, shopping)
- Transportation
- Basic medical monitoring and care (e.g., drug administration and tracking, food and liquid intake tracking, vitals monitoring)
- Administration (e.g., insurance)
- Care for kids and/or pets
- House sitting
WHO IS AVAILABLE TO HELP
Family members are often the first call to offer caregiver support. Neighbors and good friends often stand at the ready to help as well. Embrace and accept their help.
HOW TO ASSEMBLE THE TEAM
Particularly if the expected duration is long, caregivers need breaks. The caregiving process itself can be intensive and draining, and they have their own daily needs to attend to as well.
It is not uncommon to have multiple sequenced (one after another) caregivers during a four to six-week SCT treatment. However, another way to think about assembling your caregiver team is to line them up to work in parallel and together. You may be able to extend the duration of each caregiver if their tasks are narrower in scope. In addition, assign tasks consistent with each caregiver’s skills.
In my situation, I needed to prepare for having a SCT on an outpatient basis. I was extraordinarily fortunate to have four family members live with me throughout the entire treatment process. We figured it would be most productive to allocate responsibilities based on skills and that we would build in breaks from the intensity. Here’s how my caregiver team looked:
- My Dad. He was in charge of room and transportation. We needed a place to stay for five people for up to six weeks (we found a fantastic transplant-friendly house through HomeAway near the Mayo Clinic in Rochester). We also needed transportation to get all of us to/from Rochester, and determine how best to get around during our stay (a combination of fly and drive so that we had a car). Four of us were coming from the Washington D.C. area, and one from the Los Angeles area. Lots of logistics to consider.
- My Mom. With her strong organizational skills and squeamishness towards all things medical, she was in charge of all things administrative and insurance-related. She was in charge of making the list of things we needed to bring or buy to set up the household and kitchen. She brought favorite recipes so we could more easily muster grocery lists. In addition, she would collect receipts, track mileage, and made sure there was good coordination between our insurance provider and Mayo Clinic. This is a procedure that requires advance authorization and is expensive, so attending to the financial aspect is important.
- My Brother. He is three years younger than me (20, and I was 23), studying pre-med with a keen interest in becoming a physician, in addition to a strong interest in sports and nutrition. His role was three-fold: exercise for all of us (myself included), nutrition, and assist in monitoring my vitals and food/liquid intake. Our rental house neighborhood was flat and had sidewalks, offering an easy way for all of us to get some fresh air even if just for 15 minutes at a time. We also found a local fitness club that we could join for a month-to-month low cost, offering another way for the caregivers to rotate to work up a sweat and work off stress.
- My Aunt. Being an oncology pharmacist, she was the obvious pick to administer my drugs, which were extensive, and monitor my vitals and food/liquid intake. In addition to the required drugs, there was also the as-needed drugs for pain, nausea, fever, etc. that she would collaborate with the Mayo medical team. Her expertise was priceless, particularly during those days when things were most difficult.
For our two pups, we found an extraordinarily loving “free range” place that lets the pups play with other like-sized pups all day, and then boards them at night. It gave us great peace of mind knowing they weren’t caged all day and night for a month. In addition, we arranged for them to send us weekly pictures, which quickly became something to look forward to.
Once we began the SCT process, I worried about nothing other than myself. I left it to my caregiver team to do all of the worrying, errands, purchasing, preparing, communicating with Mayo, etc. I loved having my family around, as I found it extraordinarily comforting and appreciated their attempts at distracting (for example, we must have played Monopoly 20 times).
BE CREATIVE AND PLAN AHEAD
While everyone has a different situation, my biggest suggestion is to be creative, mindful of who and how many caregivers you assemble for your team, and don’t underestimate all that is required of your caregiver(s). Think about your needs, as well as their needs, expertise, and time availability to commit. Listen to any guidance provided by your healthcare team. There is no question there is a lot to plan for, but the more thought you put into it will no doubt pay off in your experience. After all, while you are going through treatment this will be the last thing you are interested in or able to focus on. Advance planning is critical.
The role of a caregiver
Caregivers play an important role during the treatment of amyloidosis. In fact, so important that certain treatment will not proceed without confirmation caregiver support is in place. Educated by the medical team, caregivers are involved before, during, and after a transplant and help with basic day-to-day medical and practical issues, as well as provide emotional support. During the transplant the care needs are most intensive, requiring availability 24/7.
Hear first-hand from Mackenzie and Dr. Betsy Mencher who discuss their thoughts about the role of a caregiver. Mackenzie speaks from the perspective of a patient, and Dr. Mencher shares her experience as the caregiver for her husband.
Save A Life
Be The Match is a wonderful organization that helps match bone marrow donors with patients in desperate need of a life-saving bone marrow transplant. Check it out. You can help save a life.
Join the bone marrow registry today.
https://bethematch.org/support-the-cause/donate-bone-marrow/join-the-marrow-registry/
Day +100 Post-Transplant
Following every stem cell transplant, time is measured by “Day +” followed by how many days have passed. For example, Day +365 is one year later. Another important milestone is Day +100, which is when patients return to re-test and compare results against pre-transplant test results and determine the impact of the treatment.
Hear from Mackenzie what her Day +100 visit back to the Mayo Clinic was like, and how it went.
Recovering From A Transplant
Recovering from a stem cell transplant is a rough ride. The good news is it doesn’t last forever before you begin to feel better. The bad news is you’ve got a few tough days to go through.
Have a listen to Mackenzie’s experience post-transplant and her recovery.
