Soonja Roberson
Physician Assistant
Stem Cell Transplantation
The University of Texas, MD Anderson Cancer Center
Hi, I am Soonja Roberson. I am a physician assistant at The University of Texas MD Anderson Cancer Center in the Department of Stem Cell Transplant and Cellular Therapy. Today, we will be discussing stem cell transplants.
Upon completion of this lesson, participants will be able to: describe the purpose and methods of stem cell transplant; define HLA typing and identify the differences between various kinds of matches; identify possible complications of stem cell transplant.
Hematopoietic stem cells are progenitor cells found in the bone marrow. They have capacity for self-renewal and the ability to proliferate and differentiate. These cells are denoted by flow cytometry, by cell surface marker known as CD34.
This is a diagram of normal hematopoiesis. At the top, you will see a pluripotent stem cell has the ability for self-renewal and the ability to differentiate into both myeloid and lymphoid cell lines. The myeloid phenotype will give rise to red blood cells, platelets, macrophages, eosinophils, basophils, and neutrophils. The lymphoid cell line will give rise to T-cell lymphocytes and B-cell lymphocytes that are responsible for antibody production.
There are many benefits to stem cell transplant. They give you the ability to give high doses of chemotherapy. You also can transfer immune competent cells known as the graft from a normal donor to an immune incompetent recipient known as the host via peripheral blood or bone marrow. Stem cell transplant relies heavily on a donor's immune system to produce a heavy graft versus tumor effect rather than relying solely on chemotherapy alone.
There are several types of transplants. The first is autologous, in which the recipient's own stem cells are used. In this type of setting, there is a lower incidence of treatment-related mortality. Therefore, this treatment can be given in patients of older age. However, the downside is there is a higher risk of relapse and a relatively low rate of long-term complications. In the allogeneic setting, you use donor-derived stem cells. In this setting, there is a higher rate of treatment-related mortality; however, a lower risk of relapse and a higher rate of short and long-term complications. More commonly now is umbilical cord blood, which is also easily accessible, but has the potential of causing more infectious complications.
The timing of transplant is very critical. Transplant must be done at the maximal tumor response. Hence, patients should either be in a complete remission or a very good partial remission, which means greater than 50% decrease in disease burden. The patient can have no active infections at the time of transplant, no evidence of CNS or leptomeningeal disease, no uncontrolled chronic illnesses. They must have adequate organ function. They must have an adequate performance status, meaning they must be able to perform activities of daily living without significant side effects. And you must have an identified donor in the allogeneic setting, and be able to collect an adequate number of stem cells.
There are many indications for stem cell transplant. Most commonly transplants are done for patients with high-risk leukemias. In that setting, those patients either have induction failure, or who have poor risk cytogenetics, who have relapsed disease after standard chemotherapy, or who have treatment-related myelodysplastic syndrome, or AML, or who have high-risk ALL, meaning they have the MLL gene mutation or Philadelphia chromosome by molecular or FISH testing. In addition, patients with tyrosine-kinase resistant CML or blast crisis, refractory CLL or transformed large B-cell lymphoma, refractory or relapsed Hodgkin's lymphoma, relapsed Hodgkin's lymphoma, and chemosensitive multiple myeloma.
There are several types of preparative regimens for indication for transplant. This means the chemotherapy that the patient is receiving prior to their stem cell collection. The chemotherapy preparative regimen can either be ablative or reduced intensity or non-myeloablative. Ablative means that the bone marrow is completely ablated by the chemotherapy. This is typically used in myeloid and lymphoid malignancies and is reserved for younger and healthier patients because the treatment is much stronger. The therapy is very highly immunosuppressive. Therefore, there is more risk of toxicity, but, hence, less risk of relapse. In the reduced intensity setting, this is typically reserved for patients with lymphomas, myelomas in older patients with leukemia. Most of these patients are heavily pre-treated or have had a prior transplant. Most of these patients are also older. However, reduced intensity also causes some immunosuppression. There is, however, less toxicity, again because the therapy is less high dose and because the therapy is less high dose there is a potential risk of rejection.
Let's first discuss autologous transplant in detail.
In the autologous setting, we use the patient's own stem cells. This can be collected either via peripheral blood or bone marrow stem cells collected prior to the high-dose chemotherapy that will be given. This type of treatment is indicated in chemosensitive, recurrent Hodgkin's lymphoma, chemosensitive, low-grade, or intermediate grade lymphomas, and multiple myeloma.
As stated before, the stem cell collection is done prior to the high-dose regimen being given. The cells again are collected via either peripheral blood or bone marrow harvest. If the cells are collected via peripheral blood, the bone marrow needs to be stimulated by a growth factor known as Neupogen®. In some cases, we also give chemotherapy in addition to the growth factor. By giving chemotherapy in addition to the growth factor, particularly in patients with lymphoma who have been heavily pretreated, it helps yield a higher CD34 count and hence increases the number of stem cells collected pretransplant. Once the cells are collected, they are cryopreserved until the time of transplant. An adequate stem cell dose in the autologous setting is greater than 2 million CD34 cells/kg of the recipient's weight. In the allogeneic setting, the cell dose is greater than 4 million CD34 cells/kg of the recipient's weight.
The autologous transplant process is very simple. First, the cells are collected as discussed before. The high-dose chemotherapy is given over a week's time. Within 24-48 hours after the completion of the chemotherapy, the stem cells are infused like a blood transfusion via central venous catheter. It takes about 2 to 3 weeks for the peripheral blood counts to recover following the high-dose chemotherapy. During this time, patients are susceptible to infection and, therefore, prophylactic antibiotics are given as well as growth factors during their peri-transplant and post-transplant course.
In contrast, allogeneic transplant...
...relies heavily on stem cells from a genetically HLA compatible donor. This donor can be either from the family, known as related, or from the National Marrow Donor Program, or the unrelated donor registry. These cells also can be collected via peripheral blood or bone marrow. Once again, chemotherapy is given prior to the stem cell infusion. In this setting, however, patients are given anti-rejection or immunosuppression medication prior to the stem cell infusion and are continued on the immunosuppressive medication up to 6 months after the stem cell infusion.
There are many benefits to an allogeneic transplant. First, is an allogeneic transplant provides a strong graft versus tumor effect and hence lowers the rate of relapse for the patient. In turn, this also increases the overall survival for the patient. However, there are many complications that can be fatal in the post-transplant setting. This includes graft versus host disease, which we will discuss later, infectious complications, and graft rejection or graft failure.
HLA donors require a stringent HLA typing. HLA stands for human leukocyte antigen. It is DNA-based typing found on chromosome 6. We look at the major histocompatibility class I and II. Class I is denoted by the loci A, B, and C. Class II is denoted by the loci DR, DQ, and DP. Each individual inherits one set from each parent. And hence for a perfect match we would like to have a perfect 10/10 match. If we look at the primary three loci that causes the most increase in graft versus host disease: A, B, and DR, the minimum number of match you must have to have a successful transplant is 5 of 6, meaning you can have one mismatch in either one of those loci. If you look out further to class II, including DQ, the minimum match you can have is 10, and so on and so forth. This type of blood test is done on peripheral blood and takes about 2 weeks to have the final results.
When assessing the donor, we look at their health status. We would like younger donors. We assess their past medical history. We look at infectious disease testing including hepatitis and HIV serologies. We look at CMV serology, pregnancy history, and the donor takes a thorough physical examination.
There are many types of stem cell sources: peripheral blood, bone marrow, and umbilical cord blood.
Peripheral blood is easily collected. It is collected via venous catheter in the vein after stimulation by Neupogen® because these cells are in the peripheral blood and are more susceptible and have seen antigen before, therefore, making them more immune competent, once given to the patient, the patient tends to engraft quicker, which means their counts tend to recover quicker after infusion. Because these cells are more immune competent and have been exposed to antigen, there is an increased risk of graft versus host disease for the patient. Unlike peripheral blood, in the bone marrow setting, these cells are collected via general anesthesia in the operating room. These cells are more Naïve, they have not been circulating in the peripheral blood, and, therefore, have not seen antigen and, therefore, once given to the patient, the patient's counts are slow to recover. This increases their risk of infection and bleeding complications post-transplant. But because these cells are Naïve it decreases the patient's risk of graft versus host disease.
The third type of stem cell source is umbilical cord blood. They are many advantages to umbilical cord blood. First, cord blood units are found throughout the world in multiple banks throughout the United States and the world in general. These cells are collected noninvasively after the baby is born by an OB/GYN. Cord blood is minority targeted, generally selected for patients of African-American, or Asian origin. Because these cells are very immune-incompetent and very Naïve, there is less DNA --- there is less stringent donor HLA typing, and these cells tend to cause less graft versus host disease. The disadvantage to umbilical cord blood is that these cell doses are small, and, therefore, once given to the patients it takes their counts many more weeks to recover and hence there is slower engraftment. Because the counts are slow to recover, patients are at more risk for infectious complications and of risk of actually rejecting their graft.
In the post-transplant setting...
...there are multiple complications. Obviously, these include infections due to the severe immunocompromised patient, graft versus host disease, organ damage from the chemotherapy, potential risk of graft failure or rejection, and also relapse is a major concern. In the infection setting, infections can be the major cause of mortality after transplant. In their early post-transplant course, meaning within their first 100 days, viruses are the most common infections that affect our patients. These include herpes simplex virus, cytomegalovirus, and varicella zoster. Also, bacterial infections are still common in the peri- and post-transplant course. In the late post-transplant course, meaning beyond day 100, Epstein Barr virus is the common viral complication and also fungal infections, particularly aspergillus, becomes a problem.
To prevent these problems, the patients are given prophylactic antibiotics up to six months post-transplant, to cover both viruses, bacterial, and fungal infections. In addition, we also prophylax for pneumocystis infection. There is also stringent surveillance for CMV reactivation. And some patients are also prophylaxed against cytomegalovirus, particularly if they have had previous CMV infection.
Graft versus host disease, as discussed before is a major complication post-transplant. So what is graft versus host disease? It is an inflammatory response mediated by the donor cells, which is the graft reactivity to the host cells characterized by antigen presentation and T-cell recognition. There is a strong cytokine release due to damage of the patient's tissue from the chemotherapy. This cytokine release leads to an inflammatory response that causes tissue damage for the patient. Graft versus host disease is highly linked to the HLA compatibility. Hence, the more incompatibility you have, the more risk of graft versus host disease. Graft versus host disease, or GVHD, occurs in approximately 50% of our patients despite being prophylaxed against it. We describe GVHD as either acute or chronic, depending on the time at which it occurs after the transplant. In the acute setting, this occurs within the first 100 days after the stem cells are infused, and in the chronic setting, this occurs after the first 100 days. If graft versus host disease is not controlled or treated properly, it can be life threatening. And again, as stated before, we do give prophylaxis but, once patients develop the GVHD, they must be treated aggressively.
There are many risks for graft versus host disease. First, age is major risk, the older the patient the greater the risk. HLA matching, the more mismatches you have, the more risk of GVHD you may have. The stem cells source, peripheral blood causing more graft versus host disease than bone marrow, again due to the fact that peripheral blood is more immune competent than bone marrow. Gender mismatching, we typically like to have a female donor give to another female donor because females who have had children produce more antibodies and this produces more risk of graft versus host disease when given to a male recipient. The intensity of the preparative regimen, the ablative regimens tend to cause more graft versus host disease because there is more tissue damage from this strong chemotherapy, which can incite graft versus host disease and the type of prophylaxis that is given to the patients.
There are many kinds of GVHD manifestations. The skin is a common organ system affected by graft versus host disease. In the acute setting, the typical presentation can be a fine maculopapular rash that is erythematous and it may or may not be pruritic. In the chronic setting, we see more hyperpigmentation and scleroderma, much like autoimmune scleroderma. In the GI tract, GVHD can affect anywhere from the mouth to the rectum. Oral symptoms can include sensitivity, poor appetite, [and] decreased saliva. You can also have abdominal cramping, nausea, vomiting, diarrhea, weight loss, and malabsorption. GVHD also affects other organ systems including the liver, which causes hepatitis and jaundice. Pulmonary system is affected, which results in shortness of breath. Eyes can be affected, which can cause dry eye syndrome, also dry, irritated eyes. And also the fascia can be affected, which leads to joint stiffness, pain, and swelling.
This is a picture of acute cutaneous graft versus host disease evidenced by erythema in a macular rash that may or may not be pruritic.
This is a picture of hyperacute cutaneous graft versus host disease. Hyperacute meaning the GVHD has occurred within the first 30 days after stem cell infusion. This is a very angry, red, painful rash the patient has experienced after the stem cell infusion.
This is an example of ocular graft versus host disease where the patient's eye is very red, irritated, and injected [speaker intended to say "infected"].
Oral graft versus host disease manifested by pain [and] redness in the oral mucosa. There are also can be changes on the hard palate and tongue.
The clinical diagnosis of graft versus host disease can be made by the history and physical examination, although biopsy to get a pathological diagnosis is also essential. Most commonly, we can easily do skin, liver, and bowel biopsies. For the lung, we typically rely on pulmonary function testing looking at residual volume and forced vital capacity. And we also use high-resolution CT scanning to assess any abnormalities within the lung parenchyma.
Treatment for graft versus host disease can either be systemic or localized depending on the extensiveness of the disease. If there is more than one organ system affected, high-dose steroids are given. This is given in the form of Medrol®, at 1 to 2 mg/kg of the patient's weight. Once the patient starts to respond in their clinical symptoms then the Medrol® is tapered. There is about a 50% response rate when steroids are given up front. In addition to steroids, however, immunosuppression must also be given in the form of tacrolimus. Blood levels of tacrolimus must be monitored closely. Supratherapeutic levels can cause both neuro and renal toxicity. Subtherapeutic levels can cause inappropriate treatment and inappropriate response of the clinical symptoms. In addition to oral medications, a procedure called photophoresis can also be utilized for both skin and GI symptoms. In this setting, a patient is taken to the apheresis unit, their stem cells are pulled out like dialysis. The cells are injected with psoralen, which makes them sensitive to UV light. The cells are then zapped with UV light and then re-injected into the patient. In this setting, your goal is to try to get the patient off of the steroids as soon as possible. Photopheresis is given over several months, two to three times per week, until the symptoms have subsided. For localized treatment, particularly the eyes, mouth, and skin, it is easy to use either eye drops or mouthwash or topical creams.
In the event that steroids are not successful, there are second-line agents that patients can --- that can be used for patients. This includes mycophenolate mofetil also known as CellCept®, infliximab, which is mostly used for the GI tract, cyclosporine, and anti-thymoglobulin. All these regimens are successful as a second-line agent, but if patients do not respond to these second-line agents there is about 10% long-term survival.
The goal of graft versus host disease treatment is to, number one; suppress the immune system without suppressing the graft. So, if a patient has a major flare of graft versus host disease, you have to get control of the immune response of the graft cells. You want to suppress the cells overactiveness, but you do not want to suppress the cells too much such that the patient may relapse. You need to follow the tacrolimus levels again because supratherapeutic or subtherapeutic levels can be detrimental. You also want to improve the patient's quality of life. Sometimes, in some cases, patients have severe nausea, vomiting, weight loss, cachexia, bad skin rash, bad mouth pain, and so you want to control the symptoms, either again with systemic treatment or localized treatment. Because the patients will be immunocompromised with the immunosuppressive medication, patients must be prophylaxed against [speaker intended to say, "with"] antibiotics. Once again, you want to try to prevent or decrease the incidence of superimposed infections. You also would like to decrease the incidence of secondary complications from the high-dose steroids, namely diabetes, avascular necrosis of the hips or shoulders, and also osteopenia, and osteoporosis.
Another complication of stem cell transplant is graft failure or graft rejection. There are two types of graft failure. The first is primary graft failure. This occurs when the patient is given high-dose chemotherapy. The stem cells are infused, but the patient's counts do not recover and hence the patient remains pancytopenic for several months --- for several weeks (excuse me). When assessing the bone marrow examination, the bone marrow biopsy itself would be aplastic. The second form of graft failure is secondary graft failure. This occurs when the patient does have initial engraftment, which means their counts do recover after the stem cell infusion. However, over the subsequent weeks, the blood counts slowly decline. When assessing the patient's bone marrow or peripheral blood, you notice gradual decline in the amount of donor cells in the patient's blood. This is called secondary graft failure. In contrast to graft failure, there is also graft rejection in which the patient is given high-dose chemotherapy, stem cells are infused, the patient's counts recover, but when assessing the bone marrow or peripheral blood, the recovered counts are the patient's and not the donor's. And hence the patient has rejected the graft and there are no graft cells in the donor's specimen --- (I am sorry) there are no graft cells in the patient's bone marrow or peripheral blood.
The final and almost worst complication is unfortunately relapsed disease. In this setting, there are still potential treatments for the patient. The patient can either choose to pursue supportive care and not receive any further treatment depending on how debilitated they are from their primary transplant. Another treatment is to reduce or discontinue the immunosuppression. So in the setting of relapse you can always taper or decrease the immunosuppression, i.e., the tacrolimus, and try to incite some graft versus host disease. If the patient is physically capable, you also can give chemotherapy by itself and see what kind of response you get in the patient's disease.
The fourth and final treatment is called a donor lymphocyte infusion. A donor lymphocyte infusion or DLI is when you give T-cell lymphocytes to the recipients. This is either given with or without chemotherapy. The T-lymphocytes are collected from the donor without any growth factors or any other stimulation. The T-cells are infused into the recipient without any immunosuppression or no tacrolimus. You hope to incite a strong graft versus tumor effect, but you also can increase or produce graft versus host disease. The reason being, is again, you are giving T-lymphocytes without any immunosuppression. So the risk of graft versus host disease increases. This type of treatment is indicated in the relapsed disease setting, in [a] progressive disease setting, and in patients with residual disease after transplant. A DLI is absolutely contraindicated if the patient has active graft versus host disease. By giving a DLI to a patient with active graft versus host disease, you can incite fatal graft versus host disease.
In the late phase of transplant, there can be other complications outside of infections. This can include secondary malignancies, i.e., head and neck malignancies. You also can develop cirrhosis or other organ damage. And this can be multifactorial either from prior chemotherapy, transfusion, hepatitis from drugs, and also graft versus host disease. Again, late infections are critical, CMV infection, fungal infection, encapsulated bacteria, and also Epstein Barr related infections. In the post-transplant setting, you also want to make sure you re-vaccinate patients. Once patients are given their high-dose chemotherapy, they lose all antibodies of prior vaccinations and, hence, once they have no active infections, and are off immunosuppression, there is a re-vaccination schedule. This includes pneumococcal vaccination, influenza, tetanus, [and] hepatitis B. In the autologous setting, these vaccinations are given at one year after transplant. In the allogeneic setting, these vaccinations are given at least six months after discontinuation of the immunosuppression. Again, the patient can have no active infections and no active graft versus host disease. In addition, in order to assess how successful the transplant has been, you assess the chimerisms. Chimerisms are quantitative analysis of donor cells that can be assessed either via peripheral blood or bone marrow. Staging is done every three months post-transplant in the first year, and then every six months thereafter, on year two and three, and then annually. Bone densities and pulmonary function testing is also assessed at six months and then clinically as indicated.
This is a diagram of the allogeneic transplantation in detail. The patient is given an ablative hematopoietic regimen. The first figure you will see denoted by A is the patient's blood cells. The cells denoted by A with a subscript 1 are the leukemia cells. The patient again as stated above is given a preparative regimen. This B is denoted by the donor cells that are given to the patient. When assessing the patient, you note ---there is noted to be some cells denoted by B in the recipient. However, the patient is not full donor yet and there sometimes, a donor lymphocyte infusion is required, in addition to immunosuppression withdrawal, in order to incite complete donor chimera as evidenced by the last figure.
In conclusion, stem cell transplant is an option for treatment for various hematologic diseases. Stem cells can be collected from donors, umbilical cord blood, or from the recipient, depending on which type of transplant the patient will receive. Ablative or reduced intensity chemotherapy is given prior to the stem cell transplant. In addition, there are potential advantages of graft versus tumor effect in the allogeneic setting. However, there are various serious complications that occur in the post-transplant setting to include graft versus host disease, organ damage, and graft failure. With all this being said, allogeneic transplants have the best chance of improving the patient's overall survival, particularly in patients with relapsed disease who most likely will no longer respond to standard chemotherapy. Thank you very much for your time and attention. Please let us know if this presentation has been useful to you.
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