Allogeneic

Coming soon.

Autologous

Autologous Stem Cell Transplant for the Treatment of T-Cell Leukemia and Lymphoma

T-cell lymphomas and leukemias are diseases that are responsive to traditional chemotherapy – in addition to the newer targeted agents that continue to improve the outcomes of patients with these diseases.  While significant progress has been made with many new agents added over the past few years, the traditional chemotherapy agents continue to have a role in the management of these diseases.  Most importantly, these medications continue to enable cure for some subtypes of T-cell lymphomas and leukemias. 

One of the first lymphomas that was shown to be extremely sensitive to agents that disrupt the ability of the cell to grow and divide was a disease named Burkitt Lymphoma, a type of non-Hodgkin lymphoma.  More specifically, this is a type of lymphoma that occurs most commonly in sub-Saharan Africa in regions where malaria is also common.  In the 1960s, oncologists from the United States and Europe traveled to Africa and found that patients with Burkitt lymphoma responded very well to a single dose of a single chemotherapy medicine such as cyclophosphamide, methotrexate, vincristine and melphalan.¹  Encouraged by these results, these oncologists began using these same medications in the treatment of children with acute lymphoblastic leukemia – one of the most notable advances in the early days of chemotherapy. 

While early trials of chemotherapy had their successes, the side effects of these agents were realized at the same time.  Most importantly, these agents that were effective at killing the lymphocytes that cause lymphomas and leukemias also caused a temporary stop to the production of normal blood cells – namely white blood cells, red blood cells, and platelets.  The bone marrow, the site of production of these cells, makes billions of blood cells per day.  Any interruption in this supply caused a decrease in the blood counts – and each caused a respective symptom in patients.  A decrease in white blood cells, most importantly the neutrophils which help to fight bacterial infection, can make patients more susceptible to infections.   A decrease in red blood cells, which carry oxygen and nutrients to the body cells, can cause fatigue and shortness of breath.  Finally, a decrease in platelets, which help to clot the blood, can make patients more prone to bleeding and bruising.  These side effects of the traditional chemotherapy medications limited the doses that could safely be given to patients. 

However, around the same time as the development of these agents, in the midst of the cold war, there was significant interest in preventing the side effects of a potential nuclear attack.  Those that are distant enough from the site of a nuclear blast to survive, but close enough to be affected by it, have injury to their bone marrow from the associated radiation. Individuals with significant radiation exposure also develop low blood counts – and the consequences in those that are severely affected can be fatal.  Since the recognition of the role of the bone marrow in the production of blood cells – namely the hematopoietic (or blood-forming) stem cells within that space – was being recognized at the same time experiments were initiated to determine whether patients exposed to fatal doses of radiation could be rescued from inadequate blood cell production. ²

An early pioneer in this field was Dr. E Don Thomas who led the way in determining whether the replacement of bone marrow could rescue individuals from the side effects of high doses of radiation.  While it was not fully appreciated at the time, investigators noticed that by infusing cells obtained from the bone marrow or spleen, that dogs who were exposed to lethal doses of radiation could be successfully rescued from the anticipated effects (dogs were found to be the best way to learn more about this process because of important similarities between human and dog immune systems).  With this information, Dr. Thomas proceeded to learn more about how to best use this therapy to benefit human patients.  Eventually, he demonstrated that the infusion of appropriate bone marrow cells could reliably recover the blood counts of patients exposed to what otherwise would have been lethal doses of chemotherapy and radiation.³ 

Since the low blood counts caused by chemotherapy had previously prevented the safe administration of higher doses of these medications, Dr. Thomas’ discoveries enabled doctors to learn more about whether this would help patients with leukemia and lymphoma.  In fact, studies confirmed that by giving higher doses of chemotherapy to diseases sensitive to these medications, some patients that otherwise would not have survived could be cured of their disease.  Thus, high-dose chemotherapy and stem cell rescue enabled the treatment that we now title autologous stem cell transplant.

Autologous stem cell transplant is a process whereby blood-forming (hematopoietic) stem cells are first collected from the patient and cryopreserved with the use of a chemical called DMSO.   Then, patients receive high-dose chemotherapy that enables some patients to be cured that otherwise would not be – and would cause significant decrease in blood counts that would likely be fatal.  However, shortly after the completion of chemotherapy the patient’s own blood-forming stem cells are thawed and reinfused into the patient in a process resembling a blood transfusion.  These stem cells remember their home, and find their way back to the bone marrow space where they once again produce healthy blood cells.  The white blood cells, or neutrophils, take 10-14 days on average to return with the platelet count rising a few days later.  The red blood cells take slightly longer to return, but do so reliably in the majority of patients.  While this process does have significant risk, it can also have significant benefit for patients with T-cell lymphoma and leukemia. 

When talking about any therapy for patients with these diseases, it is very important to discuss how differently the types of lymphoma and leukemia respond to various treatments.  In fact, there are at least 67 different types of lymphoma according to the current classification system.  So, when we try to determine how helpful autologous stem cell transplant is for a specific patient, it is necessary to consider the specific type of T-cell lymphoma or leukemia that they have.  For some patients this treatment is recommended, and for others it is not.  The best way to determine this is to discuss it with your doctor and/or with a doctor that performs the stem cell transplant procedure. 

For example, patients with anaplastic large cell lymphoma that are negative for the ALK rearrangement will not usually be recommended to undergo autologous stem cell transplant if they respond well to their first combination of chemotherapy.  Alternatively, many types of T-cell lymphoma can benefit from autologous stem cell transplant if it returns after an initial course of treatment but remains sensitive to chemotherapy, and they are able to enter a second remission. ⁴

While the process of autologous stem cell transplant can provide significant benefit to patients, it must be carefully considered.  While the stem cell rescue prevents significant complication for most patients that undergo this type of treatment, it is not able to prevent these events in all patients.  Some individuals will die from this treatment even with the best of care and consideration prior to proceeding.  Markers that provide stem cell transplant physicians with an indication of how likely this is to happen include other medical conditions that the patient has including heart, lung, liver, kidney, and infectious diseases.  For this reason, any patient that undergoes this treatment has extensive testing beforehand to make sure they are a good candidate.  In addition, the overall fitness of patients is a consideration.  For this reason, I recommend all of my patients participate in regular physical activity (as their treatment allows) both to enable possible stem cell transplant, but also because regular physical activity has been shown to increase how long patients live with many types of cancer.  Regular exercise also improves how well patients tolerate various types of treatment. 

Because of the significant risks of this therapy, most transplant centers will have specific requirements that must also be met.  First, patients must have a caregiver that is a family member or friend who will be with the patient through at least the first few months of the transplant process.  This has been shown in prior studies to increase the survival rate of patients that undergo stem cell transplant, supporting this requirement.⁵  Similarly, because patients that undergo stem cell transplant may need treatment in a timely manner most transplant programs will require that patients live within 30-45 minutes of the center for at least the first few months after the stem cells are reinfused.  Local housing options are available for patients that live farther away, and every attempt is made to provide this resource in a cost-effective manner.  (an example is the American Cancer Society Hope Lodge www.cancer.org/treatment/supportprogramsservices/hopelodge)

Once all of these requirements have been evaluated and a patient is selected to undergo autologous stem cell transplant, they proceed to stem cell collection.  This occurs either after chemotherapy with the help of a natural growth factor called GCSF or with GCSF alone that causes the blood-forming stem cells to leave the bone marrow and circulate in the blood stream.  On the right day, which can vary patient to patient, these stem cells can be collected by removing blood from the body and processing in an apheresis machine.  After the stem cells are collected, the rest of the blood is returned to the body in a process that resembles dialysis.  This process requires significant flexibility, as each patient’s response to treatments can vary and the specific day that they are ready to collect can vary as well.  Most patients are able to successfully collect enough stem cells to undergo the treatment, though some are not because of the prior treatments that they have received for their cancer.  In order to proceed to the transplant, patients must be able to store and freeze at least 2- 2.5 million stem cells per kilogram of body weight.  This means that an average individual must collect almost 150 million of these blood-forming cells to proceed. 

Once the cells are collected, the patient can proceed to stem cell transplant.  This usually involves admission to the hospital for about three weeks.  Based on the specific type of lymphoma or leukemia, 7 days are usually spent receiving the high-dose chemotherapy and 1-2 days following that treatment the stem cells are reinfused into the body.  The next two weeks is the time where patients experience the side effects of the chemotherapy which can include infections, need for blood transfusions, nausea, diarrhea, mouth sores, hair loss, and injury to other organs.  While some have significant complications, most patients are able to recover from the process with most of these side effects resolving once the white blood cell count increases – about 10-14 days after the stem cells are infused.  Once the white blood cell count recovers and the patient engrafts, they can be discharged from the hospital.  Following, they require frequent clinic visits as they gradually increase their strength and recover from the process. 

While it is certainly a significant process and not one to be undertaken without careful consideration and consultation by a doctor experienced in stem cell transplant, it can provide significant benefit to patients with a disease that would not be cured with standard approaches.   Autologous stem cell transplant is but one of many encouraging therapies for patients with T-cell lymphoma.  If you or your loved one has T-cell lymphoma, consider asking your doctor whether it would be appropriate for you to discuss stem cell transplant for the treatment of your disease. 

References

1. Magrath I. Curr Op Onc 2009;21:462
2. Jacobson L, et al. Proc Soc Exp Biol Med. 1949;70(4):740-2
3. Thomas ED et al. JCI 1959. 1709
4. Nademanee et al. BBMT 2011. 17:1481
5. Beattie et al. PLoS One. 2013; 8(4):e61586

Matthew Ulrickson, MD

Banner MD Anderson Cancer Center

Gilbert, AZ