LEUKAEMIAS & LYMPHOMAS

What is leukaemia?

Leukaemias are cancers of white blood cells (Figure 1) . Chronic leukaemias may progress slowly over years, but acute leukaemias are much more aggressive and often lead to death within months, or even weeks. Leukaemias are subdivided according to the cell type affected. Examples are acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML). Chronic myeloid leukaemia may convert into an acute form, a process known as blast transformation or blast crisis, which is particularly resistant to therapy. Related malignant diseases of the blood cells and lymphoid tissue (lymphomas) also include multiple myeloma, myelodysplastic syndrome (MDS), Hodgkin's disease and non-Hodgkin's lymphoma (NHL).

Chronic forms of leukaemia cause symptoms such as a tendency to recurrent infections and various signs of immune deficiency. In acute leukaemia, there is an imbalance in the proportions of blood cells owing to infiltration of bone marrow and symptoms may include bone pain and enlargement of organs such as liver, spleen and lymph nodes.

Who does leukaemia affect?

Leukaemias can occur at any age, but are more common over the age of 50. Each year, about 24,500 people in Britain are diagnosed with some type of blood or lymphoid malignancy, about 6,000 of them with leukaemias (500 cases in children) and nearly 10,000 with lymphomas. NHL is the most common blood cancer (about 8,500 cases per year); some may be associated with HIV infection.

Present treatments and shortcomings

Leukaemias and lymphomas are more treatable with medicines than most cancers, although remission rates vary considerably from one type to another. Life expectancy is in many cases now much increased. Treatments depend on the type, stage and grade (degree of aggressiveness) of the disease, but generally involve chemotherapy, possibly supported by therapy with naturally occurring proteins called cytokines e.g. interferon or granulocyte colony stimulating factor (G-CSF), and, in some cases, bone marrow or blood stem cell transplantation.

A variety of chemotherapy treatments have been developed that can achieve good remission rates, and specialised cancer centres are constantly refining procedures. In favourable cases, e.g. younger patients with ALL, remission rates may be 80 per cent or more, but eventual relapse remains a problem, due to the difficulty of eliminating all of the malignant cells and the development of resistance. However, in specific situations, such as the treatment of CML with the new agent imatinib (Glivec, Novartis), very high response rates can be achieved, and clinical trial data indicate a significant benefit in survival rate at 42 months after treatment.

During the very intense chemotherapy used to induce remission of disease, and in bone marrow transplantation, side-effects such as bleeding, infections, mucositis, vomiting, liver and kidney damage may limit the doses that can be used, and supportive treatment with a variety of medicines including anti-emetics and G-CSF (Neupogen, Amgen) is given to help minimise these problems.

What's in the development pipeline?

Many new agents are being developed for the various types of leukaemia and lymphoma and only a limited number of selected medicines can be discussed here.

There is a marked need for new treatments for AML. Gemtuzumab ozogamicin (Mylotarg, Wyeth) consists of an antibody coupled to the cytotoxic antibiotic calicheamicin. The antibody half of the molecule binds to a protein on the surface of the leukaemic cells, accurately targeting the medicine to its intended goal, to maximise effectiveness and minimise side-effects.

Also being reviewed is Ceplene (histamine dihydrochloride, EpiCept). When given together with a low dose of the cytokine interleukin-2 (Proleukin, Chiron - only indicated for use in kidney cancer in the UK), this has been shown in clinical trials to lengthen the leukaemia-free survival time in people in first remission from AML. Other new agents under development for treating AML include Cephalon's lestaurtinib, and MGI Pharma's decitabine, both in Phase 3 trial. At an earlier stage, Clofarabine (Evoltra, Bioenvision), an anticancer agent already available for use in childhood ALL, is now in Phase 2 trials, as are XL999 (Exelixis), midostaurin (PKC412, Novartis) and MLN518 (Millennium Pharmaceuticals). Also at Phase 2, Lorus Therapeutics has GTI-2040, SGX Pharmaceuticals has troxacitabine and Vion Pharmaceuticals has a new cytotoxic agent Cloretazine. Although the outlook for adult AML is still poor, the number of new approaches in development is encouraging.

While the introduction of imatinib (Glivec, Novartis) marked a significant advance in treating CML, the problem of emerging resistance limits long-term survival and new treatments are still needed. Dasatinib (Sprycel, Bristol-Myers Squibb) has been developed for use in this situation. Also in advanced development is nilotinib (Tasigna, Novartis), that, like dasatinib, has shown high response rates in patients who have become resistant to imatinib. Ceflatonin (ChemGenex) is also being studied for use in these patients and has reached Phase 2 study.

Survival and quality of life are often better in CLL, as it often progresses slowly and fewer patients are given chemotherapy than in acute leukaemias. However, those with anaemia or thrombocytopenia have a poorer prognosis and may be treated with chlorambucil (Leukeran, GSK) or fludarabine (Fludara, Schering). There are currently few treatment options for those who become resistant to fludarabine, although the monoclonal antibody alemtuzumab (MabCampath, Schering) has been made available for this situation. Further compounds are however in advanced trial. Sanofi-aventis is exploring alvocidib (Flavopiridol), which has reached Phase 3. Also at Phase 3 are ofatumumab (Genmab and GlaxoSmithKline) and rituximab (MabThera, Roche), and oblimersen (Genasense, Genta).

The most frequent lymphoid malignancy, non-Hodgkin's lymphoma, is classified into many different sub-types, according to the cells that each arise from, and these may vary in their response to therapy, making progress more difficult. However, NHL is also the subject of very active research into new treatments. The introduction of the monoclonal antibody rituximab (MabThera, Roche) brought a significant improvement in survival when used together with the standard chemotherapy regimen. Roche has continued to explore the use of this agent, and it has recently been recommended by NICE for use in first-line treatment of follicular lymphoma (a specific type of NHL).

A further advance occurred when the radio-immunotherapy ibritumomab tiuxetan (Zevalin, Schering) was launched in 2004. This is coupled to radioactive yttrium-90 which destroys the tumour cells. It is indicated for use in B-cell NHL that does not respond or has relapsed after rituximab treatment. A third monoclonal antibody, currently in Phase 3 development, is ofatumumab (HuMax-CD20, Genmab and GlaxoSmithKline), which is being investigated for use in follicular lymphoma that no longer responds to rituximab.

Also at Phase 3 in NHL are enzastaurin (Lilly), which is given by mouth, bendamustine (Treanda, Cephalon), AMD3100 (Mozobil, Genzyme), which is designed to facilitate stem cell transplantation, and temsirolimus (Torisel, Wyeth), which is being studied in a different subtype of NHL called mantle cell lymphoma. Phase 2 development compounds include galiximab (Biogen Idec), mapatumumab (HGS-ETR1, Human Genome Sciences), and combinations of rituximab with bortezomib (Velcade, Millennium) or Interleukin-2 (Proleukin, Chiron).

The prospects for people with multiple myeloma have also improved with the authorisation of new treatments. Bortezomib (Velcade, Ortho Biotech), which belongs to a new class of agent called proteasome inhibitors, has been shown to lengthen the time before relapse and to extend survival (to 80 per cent survival at one year) in patients previously treated with chemotherapy, as compared with the previous standard treatment with high-dose dexamethasone (66 per cent one-year survival). Bortezomib is currently in Phase 3 study for first-line use in multiple myeloma. Also in Phase 3 study are lenalidomide (Revlimid, Celgene) and doxorubicin (Caelyx, Schering-Plough), which is indicated for use in advanced ovarian cancer and in AIDS-related Kaposi’s sarcoma.

Several other new treatments for multiple myeloma have reached the Phase 2 stage, including XL999 (Exelixis), lestaurtinib (Cephalon), mapatumumab (Human Genome Sciences), and Aplidin (PharmaMar).

The longer-term future

Although recent advances in treating leukaemias and lymphomas may seem relatively modest, they are beginning to have a very real impact on survival prospects. Monoclonal antibodies offer new ways of working against malignant cells and generally have fewer disruptive side-effects than cytotoxic medicines. Given the large number of new compounds in the Phase 3 and Phase 2 pipeline, the outlook for improved and better-tolerated therapies for this diverse group of diseases is encouraging.

FOR FURTHER INFORMATION CONTACT:

Leukaemia CARE
1 Birch Court
Blackpole East
Worcester, WR3 8SG
Phone: 0800 169 6680 (Helpline)
Website: www.leukaemiacare.org.uk