World Lymphoma Awareness Day 2019: Personalising the approach in the fight against lymphoma

World Lymphoma Awareness Day_2019

What is lymphoma?

Lymphoma refers to cancer of the lymphatic system. The lymphatic system is a circulatory network comprising a series of vessels connecting various tissues that play an important role in immunity.1 Key components of the lymphatic system include:

  • Bone marrow and thymus – tissues in which the immune cells that fight disease are created2
  • Lymph nodes and spleen – some of the sites where immune cells accumulate; many lymph nodes are located in the neck, armpits and groin.2

Similar in concept to blood moving through the circulatory system, a fluid known as lymph circulates through the lymphatic system. Along with various other roles, the lymph carries immune cells, known as lymphocytes, out of the lymph nodes and into the blood to fight infection when needed.2

Unlike leukaemia, which can occur in lymphocytes situated in the bone marrow, lymphoma develops when lymphocytes begin to divide uncontrollably in the lymphatic sites where immune cells accumulate, most commonly the lymph nodes.3 There are two major types of lymphoma (both of which can be divided further into subtypes):4

  • Hodgkin lymphoma – these lymphomas contain Reed-Sternberg cells, which are derived from B lymphocytes. The presence of this distinctive cell type distinguishes Hodgkin lymphoma from Non-Hodgkin lymphomas. Hodgkin lymphoma accounts for approximately 20% of lymphoma cases worldwide.4
  • Non-Hodgkin lymphoma –these lymphomas exist as more than 60 different types, affecting different lymphocytes and manifesting in a variety of ways; they do not contain Reed–Sternberg cells.4,5

As there are many different types of lymphoma, the symptoms can vary; however, the most common are swollen lymph nodes, fatigue, unexplained weight loss, night sweats and itching.6

Current lymphoma landscape

Since lymphoma encompasses a variety of cancers, there are multiple therapies used to treat the different types. Hodgkin lymphoma is commonly treated with chemotherapy, followed by radiotherapy in some cases.7 For non-Hodgkin lymphoma, the course of treatment is very much dependent on the subtype, but chemotherapy is still used as first-line therapy in the UK. Monoclonal antibodies and steroids are also used in certain cases of lymphoma.8 With current treatment methods, the 10-year survival rates in the UK for patients with Hodgkin and non-Hodgkin lymphoma are 80% and 63%, respectively; however, depending on the lymphoma subtype, the survival rate can vary considerably. 9,10

Personalising the approach in lymphoma treatment

Although UK survival rates for lymphoma are greater than those of other cancers such as ovarian cancer and myeloma, there is considerable variation in patient responses to current treatments for lymphoma.11,12

For some patients, chemotherapy regimens are highly effective; however, for others, they have minimal impact on cancer progression. In addition, some individuals cope relatively well with their treatment, whereas in other cases, adverse reactions are more extreme and can even be fatal. Even if the patients then go into remission, some relapse and some do not. This vast range of responses to available lymphoma treatments is largely thought to be due to intertumour and intratumour heterogeneity.12 For example, in germinal centre (GC) lymphomas (a subtype of non-Hodgkin lymphoma), 200 recurring genetic mutations that are uncommon to non-cancerous cells have been discovered; however, very few of the same mutations are observed in more than 10% of patients with GC lymphomas.13 This great variation in the genetic profiles of lymphomas may have knock-on effects on patient response rates to certain treatments. The premise of personalised or precision medicine is that if a shift can be made towards treating patients based on the specific profile of their cancer, rather than using generic therapies, treatments will become more targeted and therefore potentially more effective.13 This concept is already being applied, both in a research setting and in the clinic.

CAR (chimeric antigen receptor) T-cell therapy

One example of a personalised therapy is CAR T cell therapy. As of 2019, two types of CAR-T cell therapy have been recommended by the National Institute for Health and Care Excellence: axicabtagene ciloleucel for the treatment of diffuse large B-cell lymphoma (DLBCL) and primary mediastinal diffuse large B-cell lymphoma  (PMBCL) , and tisagenlecleucel for the treatment of refractory DLBCL . These cancers are all subtypes of non-Hodgkin lymphoma and the licensed CAR T-cell therapies are to be used only in specific circumstances in which previous therapies have failed.14 This ground-breaking treatment involves reprogramming the body’s own lymphocytes, specifically T-cells, to fight the cancerous cells, as summarised in Figure 1.15 Although this therapy does still pose the risk of serious side effects, it has been shown to be effective in individuals whose lymphomas were previously deemed untreatable.15 Since this therapy uses the patient’s own cells, it is a key example of a personalised medicine that has great potential to revolutionise lymphoma treatment in those who are unresponsive to pre-existing therapies.

Figure 1

Figure 1 - CAR T_cells

Treating based on molecular diagnostics

Additionally, approaching lymphoma on a case-by-case basis may soon affect the course of initial treatment. Profiling gene expression in lymphoma is not a common occurrence; however, as understanding of the contributions that genetic and epigenetic modifications make to various lymphoma subtypes grows, gene expression is increasingly likely to inform therapeutic decisions.13 For example, there are two main types of DLBCL – activated B-cell (ABC) and germinal centre B-cell (GCB) – both of which are commonly treated in the same fashion. However, the targeted drug ibrutinib has been shown to be significantly more effective against ABC DLBCL than GCB DLBCL, most likely because it inhibits a protein kinase that is only expressed in the ABC subtype.16

In conclusion, although personalised lymphoma treatment is not yet a reality for many, significant progress is being made in developing therapies that are tailored to individual patients, and as result, such a possibility may not be as far away as first thought.

For more information on World Lymphoma Awareness Day 2019, please visit https://www.lymphomacoalition.org/wlad.

References

  1. Lymphoma. Available at: https://bloodwise.org.uk/info-support/lymphoma. Accessed September 2019.
  2. Lymphoma Action. The lymphatic system. Available at: https://lymphoma-action.org.uk/about-lymphoma-what-lymphoma/lymphatic-system. Accessed September 2019.
  3. Lymphoma Action. What is lymphoma? Available at: https://lymphoma-action.org.uk/about-lymphoma/what-lymphoma. Accessed September 2019.
  4. Cancer Research UK. About Hodgkin lymphoma. Available at: https://www.cancerresearchuk.org/about-cancer/hodgkin-lymphoma/about. Accessed September 2019.
  5. Cancer Research UK. How doctors group non-Hodgkin lymphomas. Available at: https://www.cancerresearchuk.org/about-cancer/non-hodgkin-lymphoma/types/group. Accessed September 2019.
  6. Lymphoma Action. Symptoms of lymphoma. Available at: https://lymphoma-action.org.uk/symptoms-of-lymphoma. Accessed September 2019.
  7. National Health Service. Treatment: Hodgkin lymphoma. Available at: https://www.nhs.uk/conditions/hodgkin-lymphoma/treatment/. Accessed September 2019.
  8. National Health Service. Treatment: Non-Hodgkin lymphoma. Available at: https://www.nhs.uk/conditions/non-hodgkin-lymphoma/treatment/. Accessed September 2019.
  9. Cancer Research UK. Hodgkin lymphoma statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/hodgkin-lymphoma. Accessed September 2019.
  10. Cancer Research UK. Non-Hodgkin lymphoma statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/non-hodgkin-lymphoma. Accessed September 2019.
  11. Cancer Research UK. Cancer survival for common cancers: Survival trends over time for common cancers. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/survival/common-cancers-compared#heading-Three. Accessed September 2019.
  12. Dave SS. Genomic stratification for the treatment of lymphomas. Hematology Am Soc Hematol Educ Program 2013; 2013 (1): 331–334.
  13. Heward JAKumar EAKorfi K et al. Precision medicine and lymphoma. Curr Opin Hematol2018; 25 (4): 329–334.
  14. Lymphoma Action. First CAR T-cell therapies recommended for approval in Europe. Available at: https://lymphoma-action.org.uk/first-car-t-cell-therapies-recommended-approval-europe. Accessed September 2019.
  15. What is CAR-T therapy? Available at: https://bloodwise.org.uk/community/what-is-car-t-therapy. Accessed September 2019.
  16. Wilson WH, Young RM, Schmitz R et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 2015; 21 (8): 922–926.