LYMPHOMA AND STEM CELL TRANSPLANTS: PROCESS, RISKS, SIDE EFFECTS AND OUTLOOK

Chemotherapy and stem cell transplants have largely changed the lives of many living with lymphoma, drastically increasing life expectancy even in the most resistant cases.

This article aims to cover all you need to know about stem cell transplants for lymphoma. Read more below about lymphoma and types of stem cell transplant, their pros and cons, what the procedure entails for lymphoma patients, risks and contraindications, as well as how successful stem cell transplants are for different types of lymphoma.

What is Lymphoma?

Lymphoma refers to any cancer of the lymphatic system. The lymphatic system is a part of the body’s immune system that comprises its own circulatory system of vessels (lymph vessels), glands (lymph nodes), organs (thymus, bone marrow, spleen and tonsils) and lymphatic tissues that line many other organs. This system produces white blood cells, maintains their numbers, and regulates blood fluid balance^[1]. It also allows for foreign matter, toxins or pathogens to be contained by white blood cells, serving indirectly as a filtration system.

Types of Lymphoma. There are two main types: Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL). As the lymphoma types suggest, Hodgkin Lymphoma is easy to distinguish from Non-Hodgkin Lymphoma. The difference between HL and NHL are as follows:

• Hodgkin Lymphoma. The main defining feature of HL would be the presence of Hodgkin and Reed-Sternberg cells^[2]. These cells are thought to have arisen from faulty immature B cells. They only make up to 1% of the cancerous lymphatic tissue, which is often seen to be surrounded by non-cancerous T lymphocytes and inflammatory cells. Other differences that distinguish HL from NHL include a higher occurrence in the cervical lymph nodes and in young adults.^[3]
• Non-Hodgkin Lymphoma. In NHL, distinctions are made in terms of whether the disease is fast-paced (aggressive lymphoma) or slow-paced (indolent lymphoma), as well as the distribution pattern, which may be follicular or diffuse. In follicular lymphoma, the lymph nodes exhibit excessive malignant growth in a follicular or nodular pattern. In diffuse lymphoma, lymph nodes display normal growth patterns and are infiltrated by cancerous white blood cells. While Reed-Sternberg cells are unique to HL, it was recently discovered that similar cells can be seen in many types of NHL that have clinically distinct features^[4].

Diagnosis. There are many subtypes of lymphoma, with 5 belonging to HL and over 10 belonging to NHL. Each subtype is classified according to genetic differences, symptoms, regionality and frequently associated causes, such as subtype-specific viral infections. Blood tests, CT imaging, biopsy and sometimes lumbar puncture are used to diagnose lymphoma as well as assess the severity and stage of the disease.

Treatment Options. Treatment mostly consists of high or low-dose chemotherapy and immunotherapy, depending on the stage and severity of the lymphoma. Radiation therapy is only offered alongside chemo for patients with early-stage I and II lymphomas or for palliative treatment (e.g. pain relief). As discussed below in more detail, stem cell transplants are offered to patients in need after intensive therapy.

Prognosis. Those diagnosed with lymphoma that receive full treatment are likely to live longer than 5 years from the time of their diagnosis and to see full to partial remission as a result^[5]. Survival rates for 5 years past diagnosis for those with NHL vary between 65-90%^[6] and average 89% for those with HL^[7]. Recurrence rates are higher for aggressive forms of lymphoma (approximately 40%)^[8], the risk for which diminishes by more than half after 2 years of being symptom-free. For those with Hodgkin lymphoma, the recurrence rate averages 5-20%.^[9]

Stem Cell Transplants for Lymphoma

For many forms of lymphoma, myeloablative chemotherapy and stem cell transplantation are recommended as the golden standard of treatment. This combination poses an anticancer effect that collectively offers complete remission to many lymphoma patients.

Myeloablative Chemotherapy refers to high-dose or intensive chemotherapy that destroys cells in the bone marrow, including lymphoma cancer cells. It rapidly reduces bone marrow stem cells that give rise to new blood cells, which is why a stem cell transplantation is required afterward.^[10] Chemotherapy is also required in order to suppress and condition the immune system for stem cell transplantation, improving the outcome by reducing the risk of graft failure or rejection.

Stem Cell Grafts typically contain white blood cells from the donor that provide a graft-vs-cancer effect. Unlike the host’s white blood cells, these white blood cells are better able to detect cancer cells. When placed in the recipient’s body, they tend to react and promote the destruction of lymphoma cells.

The following sections describe different types of stem cell transplants, their pros and cons, how transplantation works, indications and contraindications, side effects and complications, as well as prognosis.

Types of Stem Cell Transplants: Pros and Cons

Stem cell transplants can be either autologous, allogeneic or syngeneic, with the former two being the most commonly used in the treatment of lymphoma.^[11] Types of stem cell transplants have been further classified according to the accompanying chemo treatment intensity as well as the number of stem cell transfusions the recipient receives. The different types are listed below with their respective pros and cons.

Autologous Stem Cell Transplants (auto SCT) make use of stem cells from the recipient.

• Pros: No risk of graft-vs-host disease and a much lower risk of graft rejection or failure.
• Cons: Associated with less anticancer benefit due to a diminished graft-vs-cancer effect. May increase the risk of recurrence if the sample contains a high number of cancerous lymphocytes. This is usually minimized with additional chemotherapy or purification of the stem cell sample, a process known as purging.

Allogeneic stem cell transplantation (allo SCT) makes use of stem cells from a donor who is a family member or genetically similar to the recipient (not an identical twin as seen in syngeneic transplantation).

• Pros: The relapse rate is much lower for lymphoma patients receiving stem cells from a donor due to a greater graft-vs-cancer effect and a reduced risk of cancer cells contaminating the graft.
• Cons: There is a risk of graft-vs-host disease and a higher risk of graft rejection or failure. The donor’s graft may be contaminated with an infectious illness that escaped prior detection.

Tandem Transplantation. This refers to undergoing two stem cell transplants in a row, which can help some patients with severe lymphoma see remission. Tandem transplants can be further divided into double autologous, double allogeneic or autologous-allogeneic transplants.

• Pros: Improved outcomes for patients with relapsed or refractory lymphoma, especially when auto-allo transplants were used^[12].
• Cons: The process takes much longer to complete than a single transplantation and may incur more hospitalization costs.

Mini (Non-Myeloablative) Transplantation. Myeloablative chemotherapy may not be indicated for elderly lymphoma patients or those severely immune compromised. In these cases, a mini transplantation or non-myeloablative transplantation may be preferable. This SCT type makes use of a lower-dose chemotherapy regimen prior to transplantation.

• Pros: Benefits include less immune suppression, bone marrow destruction and white and red blood cell reductions.
• Cons: Generally results in longer hospital stays and recovery times. Treatment is not as ideal when dealing with aggressive or late-stage lymphoma.

How Stem Cell Transplantation for Lymphoma Works

Collection. Either the recipient or donor can provide stem cells for transplantation, which are stored until required. Donating stem cells takes a few hours on average and the donor may require up to a week to recover. The donor is required to undergo general health testing beforehand to ensure they are suitable candidates. Donor stem cells are also checked to make sure they are a good match for the recipient, which greatly reduces the risk of complications.

Stem cells can be harvested from either the blood, bone marrow or umbilical cord^[13]:

• Bone Marrow. When collected from the marrow, the donor is placed under general anesthesia. The marrow is drawn out through a needle inserted into the lower back and hip. The marrow is filtered for impurities and then stored aside until required for bone marrow transplantation.
• Blood. For blood stem cell collection, the donor is often given growth factors beforehand to increase the level of stem cells in the bloodstream. Blood is drawn from the donor through a catheter connected to a filtration device, which separates out the stem cells before the blood is returned to the donor. This may need to be repeated over a few days in order to collect enough stem cells.
• Umbilical Cord. Umbilical cord blood collection does not involve a medical procedure. Excess blood from the cord is saved aside after birth for stem cell harvesting and transplantation. Cord blood stem cells are typically used for children than adults.

Implantation. High-dose chemotherapy is given to the patient several days before the transfusion takes place. Harvested stem cells are thawed before being intravenously administered to the recipient. If undergoing a tandem transplant, only half the stem cells are administered, with the other half often being administered roughly 6 months later.

Recovery. Chemotherapy is usually continuously administered throughout the recovery period in order to minimize cancer relapse^[14], promote healthy stem cell growth and reduce the risk of graft rejection and other complications. It takes around 4-6 weeks on average for new blood cells to emerge after a successful transplantation. The recipient is monitored in the hospital during this time in the event of complications.

Stem Cell Transplantation Indications and Contraindications in Lymphoma Treatment

In general, stem cell transplantation is indicated for all patients with recurrent or relapsed lymphoma. It may also be beneficial for those who experienced complete remission as a means of replenishing stem cells.

Most eligible lymphoma patients may opt for autologous transplantation, without requiring a donor. Allogeneic transplantation may be preferred in specific lymphoma cases, such as in patients with too few stem cells to harvest and in those with comorbidities that prevent making use of the patient’s own stem cells.

Frontline Use is Less Advisable. Occasionally, stem cell transplantation is recommended upfront as part of the initial treatment, especially for high-risk patients or those with either aggressive mantle cell lymphoma or peripheral T cell lymphomas. This is hardly ever recommended for those with HL. Recent studies have critiqued this approach due to advances in chemoimmunotherapy^[15], which show that the survival rates are much higher on average for lymphoma patients who receive chemo and do not opt for stem cell transplantation upfront. This highlights the need for testing before opting for a stem cell transplantation.

Tandem SCT Indications. Recurrence of HL is common after autoSCT in approximately 50% of cases^[16]. In those with refractory or relapsed HL, a tandem autoSCT has helped to improve 5-year survival rates by an average of 15-25%.^{[17] [18]}

Contraindications. There are no official contraindications to stem cell transplantation, however, emerging research points toward various applications that may not be indicated in certain lymphoma cases:

• Single SCT. A panel of experts recently concluded that autologous SCTs should be contraindicated in the case of highly treatment-resistant lymphoma in order to minimize the risk for severe complications. Despite this conclusion, other studies have shown benefits for SCTs in treating resistant lymphoma. Tandem autoSCTs may be beneficial in some but not all refractory cases^[19].
• Autologous SCT. Cases in which allogeneic transplants may be preferred over autologous SCTs include acute adult T-cell lymphoma in remission or that has relapsed, relapsed hepatosplenic lymphomas^[20], and in pediatric lymphoblastic lymphoma^[21].
• Non-Myeloablative Treatment may be contraindicated for patients with refractory or relapsed HL due to reduced survival and higher relapse rates. ^[22]
• Pediatric Burkitt Lymphoma. Children with Burkitt lymphoma should be guarded against SCT as it has been associated with a high fatality rate.^[23]

Can a lymphoma patient with cancer of the bone marrow still receive a stem cell transplant?

Yes. Cancer of the bone marrow does not necessarily impact the viability of the patient’s stem cells. Chemotherapy is also geared towards reducing the number of cancer cells present in the patient at every step of the process. The patient can also use blood stem cells, get the cancer cells removed from their harvested stem cells or opt for an allogeneic transplant.

Risks of Lymphoma Stem Cell Transplants: Side Effects and Complications

Side effects are unavoidable during the recovery phase post transplantation. Medications and other therapies may be administered during this time to reduce their severity.

Side Effects of stem cell transplantation include^[24]:

• Nausea or vomiting
• Excess bleeding
• Mouth sores or inflammation and dryness in the mouth, nose and throat (mucositis)
• Infertility (due to intensive chemotherapy)

Complications. The risk of a stem cell transplant complication depends upon the state of the patient’s immune system at the time of the transplant as well as the degree of mismatch between the donor and recipient. Any of the below complications can increase the risk of lymphoma recurrence:

• Infection. Many viral, bacterial and fungal infections are known to occur in patients as a result of stem cell transplants, usually due to the immune suppression required for treatment (as opposed to contamination). These may cause a host of other symptoms, particularly respiratory difficulties such as pneumonia. Due to the intensive immune suppression required prior to transplantation, infections may be a risk for 6-12 months after receiving stem cells. Extreme precautions should be taken to avoid infectious illness, including very strict hygiene measures. Avoid making contact with possible vectors for disease as much as possible.
• Graft-vs-Host Disease (GVHD). Unlike graft rejection, graft-vs-host disease is triggered by immune responses that arise from the foreign immune cells of the donor present in the graft. These immune cells register the recipient’s body as foreign and react. Reactions are often asymptomatic, mild or even beneficial as the foreign immune cells may start to attack the lymphoma and aid the treatment process.^[25] Too many foreign reactive immune cells, however, can lead to systemic effects and promote chronic disease, especially as the host’s immune system will be suppressed in order to undergo the transplant. Common symptoms of severe GVHD include a large rash, pain or burning sensations, nausea, diarrhoea, chronic infection and respiratory issues. Treatment usually consists of further immune-suppressing agents and, depending on the severity of GVHD, may be lifelong.
• Graft Rejection. Graft failure or rejection occurs when the immune system of the recipient recognizes the antigens (proteins) in the graft as foreign and proceeds to dispose of the graft. Rejection of stem cell grafts is exceedingly rare. The main causes of graft rejection are a depletion of T-cells in the stem cell graft, autoimmune disease (in autologous stem cell transplants) and a mismatch between the recipient and donor (in allogeneic transplants). Due to containing immature T cells, umbilical cord stem cell grafts present with the highest risk of failure. Inflammatory symptoms, infection and excess bleeding are the main side effects associated with graft failure.
• Post-Transplant Lymphoproliferative Disorders. While rare, patients that opt for stem cell transplants from a donor may contract post-transplant lymphoproliferative disorder. This disorder is usually due to stem cell contamination with the Epstein-Barr virus and is far more common in organ transplants than stem cell transfusions. Those with lymphoma are very unlikely to contract PTLDs due to being on chemoimmunotherapy, which happens to form part of the treatment protocol for this complication. ^[26]
• Blood Abnormalities. Due to chemotherapy as well as bone marrow or blood stem cell extraction, the recipient is likely to have a low red blood cell count as well as a low blood platelet count. Significantly low levels can result in transient anemia or thrombocytopenia (extremely low blood platelet count and excessive bleeding), which may extend the recovery time. Physicians tend to prescribe iron in the case of deficiency for anemia and may also provide blood-clotting medications if bleeding is severe. The blood usually returns to normal in a few weeks. However, if severe, the patient may require blood transfusions.
• Sinusoidal Obstruction Syndrome (Veno-Occlusive Disease) refers to an uncommon type of liver injury in which the veins in the liver become blocked due to toxin or drug exposure. This can be caused by chemotherapeutics and other medications administered for stem cell transplantation. Symptoms can manifest 1-6 weeks after acute toxin or medication exposure and include jaundice, edema, and weight gain, as well as abdominal pain and swelling. Other causes for similar symptoms need to be ruled out first, such as GVHD, sepsis or liver infection. Recovery can take 50-100 days and usually consists of supportive care.^[27]

Stem Cell Transplant Efficacy and Outlook

As mentioned above, the prognosis of patients with lymphoma is good. Stem cell transplants are more commonly used for high-risk patients with resistant lymphoma, those who experience relapse and as a preventive treatment for those with remission. These are the patients with the worst prognosis.

Elderly patients tend to have a worse prognosis than younger patients due to comorbid conditions and immune considerations. Children with resistant or refractory lymphoma can have either a good or bad prognosis with regard to stem cell transplantation, depending on the type of lymphoma they have^[28].

Life Expectancy After Stem Cell Transplants

Average survival and remission rates are briefly summarised below:

Hodgkin Lymphoma

• Classical HL. Most patients with classical HL (Hodgkin's lymphoma) can achieve remission by undergoing chemotherapy alone, with about 80% of them experiencing positive results. In cases of HL that do not respond to treatment (termed refractory) or where the condition relapses, chemotherapy combined with autologous stem cell transplantation can lead to remission in approximately 50-70% of patients. Among them, about 50% can survive for over 10 years on average. In patients with resistant cases of classical HL who did not achieve remission, tandem stem cell transplantation (SCT) may be considered, which has the potential to improve survival rates.

Non-Hodgkin Lymphoma

• Diffuse Large B Cell Lymphoma. Up to 86% of lymphoma comprises of B-cell types, with Diffuse Large B Cell Lymphoma being the most prominent (30-43% cases). An average of 80% with DLBCL see remission with autoSCT and high-dose chemotherapy.
• Generalized NHL. In a general NHL study, it was shown that relapse rates averaged 30% across patients of all ages who received a stem cell transplant. 3-year survival rates and mortality varied across age groups, with more than half of younger and middle-aged patients having a good prognosis. ^[29]
• Aggressive B Cell Lymphoma. In a study on 247 patients with aggressive B cell NHL, 63% survived for 3 years without disease progression after autoSCT. The average progression-free survival time without SCT is 2.1-20 months^[30]. Additionally, overall survival was seen to be doubled in 68% of the participants. ^[31]
• High-Risk T Cell Lymphoma. Studies suggest that patients with refractory and relapsed T cell lymphoma tend to live an average of 5.8 months, with an average of 21-28% of patients living over 3 years^[32]. In a larger study on 1765 refractory and relapsed T cell lymphoma patients, either autologous or allogeneic SCT led to average 5-year survival for 53-54% of patients. ^[33]

Conclusion

The life expectancy of those with lymphoma has greatly improved due to chemotherapy and stem cell transplantation, with the majority of patients able to expect complete remission and a life expectancy of longer than 10 years. For aggressive types of lymphoma, resistant cases or those that have relapsed, stem cell transplantation offers anticancer benefits that have increased overall survival rates by an average of 20%. The success of stem cell transplants depends on the patient’s immune function, their response to chemotherapy and whether stem cell grafts are a good match or not. Stem cell transplantation should be avoided for severely immune-compromised patients and children with Burkitt Lymphoma.

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