Lymphoma is the commonest haematological malignancy. Although there are now more than 40 entities of lymphoma defined under the latest WHO classification, clinically, they can still essentially be classified into two broad variants – an indolent variant where the aim of treatment is to palliate the symptoms as cure is rarely possible, and an aggressive variant, which is potentially curable and intensive therapy is usually prescribed.

Survival Outcomes in Lymphoma

Up until a decade ago, lymphoma could only be treated by conventional chemotherapy and radiotherapy. Common to both modalities of treatment are the collateral damages to normal healthy tissues seen as complications of treatment. In addition to killing cancerous cells, chemotherapy could result in indiscriminate killing of normal proliferating cells in the bone marrow, gastrointestinal tract and hair follicles, while radiotherapy could scar and cause inflammation to healthy tissues adjacent to the cancer.

With the exception of Hodgkin lymphoma, a rare subtype of aggressive lymphoma where cure rate is now over 80% with conventional chemotherapy, the overall survival of most non-Hodgkin lymphomas has not improved significantly from 1960s to 1990s, despite remarkable progress in the development of many chemotherapeutic agents.

A study by Stanford University in the 1990s had demonstrated that the survival of patients with indolent lymphoma had remained stagnant for four decades as evidenced by overlapping of their respective survival curves, and this reaffirmed the common notion at that time that one cannot defy the natural history of indolent lymphoma and treatment was essentially geared at relieving the symptoms [Figure 1].

Another landmark study on diffuse large B-cell lymphoma (DLBCL), which is the commonest aggressive lymphoma, showed that despite the development of more complex chemotherapeutic combination regimens, the cure rate of DLBCL still remained poor at 40-50% [Figure 2].

Hence, it was evident that increasingly intense regimens significantly increased toxicity while only making modest improvements in patient survival. Consequently, scientists started looking for novel approaches, and it became clear that antibodies, proteins made by the immune system, might provide the clues needed to diagnose and treat cancer.

Antibody Therapy

Antibodies are one way the immune system recognises and destroys foreign invaders. Cancer cells are not foreign, since they are part of our own body, but they often exhibit alien features that can make them appear foreign. Predicated on our improved understanding that lymphoma cells are derived from normal development of lymphoid cells and different lymphoma cell types have distinctive signatures of lymphoma-specific antigens, the use of anti-lymphoma monoclonal antibodies have now dramatically changed the treatment algorithms in lymphoma therapy.

Finally, destruction of tumour cells by tackling tumour-specific surface or intra-cellular proteins, while sparing normal tissues is now becoming a reality.

Rituximab, a customised antibody that recognises the B-lymphocyte antigen CD20, a target shared by B-lymphoma cells from most patients, was the first monoclonal antibody to be tested. It proved to be effective in treating B-lymphoma, and the elimination of normal B cells was surprisingly not harmful.

As rituximabdoes not affect other normal cells in the body, it can be combined with other chemotherapies. The addition of rituximab to chemotherapy for DLBCL dramatically improved the cure rate from 40-50% to almost 70% today [Figure 3].

Similarly, when its use was introduced in indolent lymphoma, striking improvement in survival was also noted.

In an update of the Stanford study on more than 1,300 patients with indolent lymphoma, it was demonstrated that the traditional textbook notion that one cannot defy the natural history of indolent lymphoma no longer holds true, as patients who receive modern novel treatment or are able to survive into the era of rituximab are enjoying prolonged survivals [Figure 4]. 

In fact, with the availability of rituximab and other novel agents in the treatment of indolent lymphoma, survival of such patients is now starting to approximate the survival of the healthy population, such that overall we could be converting an indolent cancer to a chronic disease.

The success of rituximab has inspired the development of many other monoclonal antibodies since multiple antigenic targets can be identified especially in B-cell lymphomas [Figure 5].

Several ‘improved’ versions of rituximab targeting the CD20 antigen are also now in advanced stages of clinical studies. These may have the added advantage of being more readily tolerated by the body as they are derived from human components unlike rituximab, which has partial murine origin, and are also able to overcome acquired resistance to rituximab.

Targeting other antigens like CD22 or CD80 has been shown to be particularly attractive in patients who have been multiply-exposed to rituximab-based regimens as tumour cells may be able to down-regulate their CD20 expression after some time.

Conjugated Antibody Therapy

In addition to naked antibodies, like rituximab, there is now a move to conjugate the monoclonal antibody to a radioisotope, an antibiotic or toxin. This may substantially improve upon the tumour cell-killing effect.

Radioimmunotherapy

Y-ibritumomab tiuxetan (Zevalin®) is now approved by HSA, and comprises a rituximab molecule conjugated to a radioisotope. It is capable of a ‘cross-fire’ tumour-killing effect whereby tumour cells that are not in direct contact with the drug could be targeted as well. Radioimmunotherapy hence allows the delivery of radiation to very specific sites of tumour involvement and avoids the complications of direct external beam radiation.

Antibody-antibiotic conjugate

Inotuzumab ozogamicin (IO) is a drug where an antibiotic, calicheamicin is conjugated to a monoclonal antibody against CD22. The antibiotic unleashes its toxic effect once the drug binds to the tumour cell.

A case study of this treatment would be patient Mr Chew, who has relapsed and refractory lymphoma. Having failed many lines of commercially available treatment courses that entailed rituximab, he was deemed terminal by his treating physician. Incidentally, a clinical study exploring the role of IO monotherapy in refractory lymphoma was launched in his treating centre. He was enrolled into this study as he had no other options in treatment. He responded remarkably to the study drug and attained a complete response without any significant side effects [Figure 6].

He has since remained in remission for three years now, and has indeed gained a new lease of life.

Conclusion

The recent advances in therapeutics of lymphoma has now allowed the possibility of formulating individualised therapy for many patients, allowing more targeted tumour attack, with fewer side effects and an overall improvement in prognosis.

This modern treatment, however, is evolving at an astonishing rate. The commercially available novel drugs are only tip of the iceberg of many more drugs that are to come. Many highly effective drugs are only available to patients in the context of clinical trials at this point in time. As such, a physician treating lymphoma now is only as good as his therapeutic armamentarium, and enrolment into clinical studies and collaborations with academia and the industry are now very integral components of lymphoma treatment