Treatment

A current overview of medications in the treatment of CLL in New Zealand

A talk presented to the CLL Advocates NZ Board of Trustees on 7 May 2020 by Dr Gillian Corbett MBChB, FRACPath, MRCP, FRACP, Trustee, CLL Advocates NZ

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It is generally accepted that CLL is not yet curable, but it is very treatable and it is usually possible to control the disease. Many patients will have a normal life-span with a good quality of life after diagnosis.

The following information was republished with permission from Leukaemia Care (UK)

When to start treatment

If you have no symptoms then you may not need to start treatment straightaway. It will be necessary for you to have regular check-ups and blood tests to monitor whether your disease is progressing. This is often called a ‘watch and wait’ or ‘active monitoring’. It is important you attend these appointments as your consultant will be able to track your condition, talk about how you’re feeling and decide on if or when treatment may be needed. Some patients who have Binet stage A CLL may never need treatment.

The indications to start treatment are:

  • Enlarging lymph nodes, liver or spleen
  • Falling haemoglobin or platelet counts
  • Constitutional symptoms such as fevers, weight loss or night sweats
  • The lymphocyte count doubling within a six-month period

A rising white count alone is not usually an indication that treatment is necessary. The aim of commencing treatment is predominantly to improve patient symptoms and/ or improve blood counts and prolong survival with a good quality of life. At present, it is not known whether the use of new combinations of treatment will actually lead to cure but there are hopeful signs this may be the case with some treatments resulting in survival of 10 years+ with no sign of active CLL in a subset of patients.

Types of treatment

The types of treatments now available have changed dramatically over the last 20 years. Initially we had only chemotherapy agents but in the late 1990’s monoclonal antibodies which target specific proteins on the CLL cell surface became available- so called immunotherapy. Since 2010 a whole new class of therapy has become available – small molecular inhibitors which either target the specific proteins that are keeping the CLL cells alive such as Bruton Tyrosine Kinase, PI-3 Kinase or BCL-2.

The initial studies over the last 20 years involved identifying which were the most effective chemotherapies and then using them in combination. Later the monoclonal antibodies were added to chemotherapy – so called chemoimmunotherapy. Now there are ongoing studies combining all 3 types of treatments, chemotherapy, immunotherapy and small molecular inhibitors.

The standard of first line treatment for most patients who require treatment for CLL is chemo-immunotherapy. If the CLL cells have a particular abnormality called 17p deletion or TP53 mutation, most forms of chemotherapy will not work very well, or at all and targeted treatment with small molecule inhibitors is usually required.

Chemotherapy

Chemotherapy is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells. It has a very high success rate in the treatment of CLL. It does not cure the disease but it gives good control for most patients. Chemotherapy will also damage some normal cells as it is toxic to all living cells, which means that there are side effects. Examples of chemotherapy agents include:

Purine analogues

Fludarabine and Bendamustine are types of drugs called purine analogue. Purine analogues affect your body’s immune system and may reduce your blood counts by affecting the bone marrow’s production of normal blood cells. While you are being treated with Fludarabine or Bendamustine, you will be carefully watched for any sign of infection. You may be given drugs to prevent some virus and fungal infections if your lymphocyte count is very low. If this applies to you then you will be given detailed information. Your haematologist or clinical nurse specialist will explain any special precautions you may need to take and will answer all your questions. Fludarabine may cause nausea and/or vomiting but this can usually be controlled by taking drugs called anti-emetics at the same time.

Alkylating agents

Alkylating agents include cyclophosphamide or Chlorambucil. They are a group of anti-cancer drugs which damage DNA and kill CLL cells. For some patients, who are less fit or who have poor kidney function, alkylating agents may be given alone but most patients have the addition of a monoclonal antibody such as Rituximab, Ofatumumab or Obinutuzumab as the combination works better than Chloranbucil therapy alone.

Targeted therapy

Treatments have been developed that target leukaemia cells more precisely than does chemotherapy, which reduces the effect of treatment on healthy cells and hence side effects. The main types of targeted therapies include:

Immunotherapy

Immunotherapy is used to ‘wake up’ your own immune system to fight the cancer. One immunotherapy technique uses monoclonal antibodies to attack and destroy CLL cells. Monoclonal antibodies are drugs that recognise, target and stick to particular proteins on the surface of cancer cells. They can stimulate the body’s immune system to destroy these cells.

The most common target for immunotherapy is a protein called CD20, which is found on nearly all CLL cells. A drug called rituximab is the most commonly used anti-CD20 treatment. Other more recently available anti-CD20 drugs include Ofatumumab and Obinutuzumab.

Small molecule inhibitors

B-cell receptor inhibitors

Like normal B-lymphocytes, CLL cells have proteins on the outside called B-cell receptors(BCRs). When a protein binds to a BCR it sends the cell a signal to divide. Unfortunately, CLL cells are particularly sensitive to BCR signals, which means they divide and produce more CLL cells. One way to stop this is to design a BCR inhibitor, which is a drug which blocks, or inhibits, the BCR signal.

There are two oral (taken by mouth) drugs currently being used which inhibit the BCR pathway:

  • Ibrutinib, which blocks a protein called Bruton’s Tyrosine Kinase (BTK)
  • Idelalisib, which blocks a different protein called phosphatidylinositol 3-kinase (PI3K)

CLL cells are more dependent on these proteins than normal cells so they are vulnerable to Ibrutinib and to idelalisib. Because of the way they work, these drugs are just as effective when a patient has a 17p deletion or a TP53 mutation. This is an important option for patients with TP53 deficient CLL because normal chemotherapy is not successful in this form of the disease and immunotherapy by itself is not very effective.

Both Ibrutinib and Idelalisib interfere with BCR signalling by triggering apoptosis in the CLL cells. Apoptosis is a natural process in which cells which are worn-out, or no longer needed by the body trigger a ‘suicide’pathway. Many anti-cancer drugs work by triggering apoptosis but cancer cells, including CLL cells, find ways to block apoptosis.

These two drugs target anti- apoptosis pathways and, despite the name, are designed to switch apoptosis back on. This means that anti-cancer drugs such as Ibrutinib and idelalisib are more able to kill CLL cells at lower doses, which means fewer side effects.

BCL-2 inhibitors

Cancer cells accumulate by switching off the process which enables cells to die- so called apoptosis. CLL cells have a very complex process for switching off apoptosis including high levels of proteins including BCL-2 and MCL-1. Venetoclax is a first in class BCL-2 inhibitor and has been shown to be effective often when other treatments fail and possibly even more effective when used in combination with chemotherapy, immunotherapy and other small molecule inhibitors. So potent is Venetoclax that you may be required to be admitted overnight to start treatment.

Immunomodulatory drugs

Also known as IMiDs, immunomodulatory drugs modify, or modulate, the way in which the immune system behaves. They have been widely used for treatment of other forms of blood cancer, and are now being studied for use in treatment of CLL. One of the advantages of IMiDs is that they do not kill all dividing cells, which means that, although they do have side effects, they are not the same as other anti- cancer drugs. This is called non-overlapping toxicity and, for patients, it means better cancer killing without more severe side effects.

Chimeric antigen receptor T cells (CAR-T cells)

Our immune system is able to kill cancer cells. However, to have developed CLL the immune system must have failed. In CAR-T cell therapy a CLL patients own T cells are removed and then manipulated in a laboratory to make them better able to kill CLL cells. They are then infused back into the patient. At present CAR-T cell therapy is not widely available and just how effective it will be in CLL is still being assessed.

Stem cell transplant

A stem cell transplant involves the use of high-dose treatment to kill as many as possible of the leukaemia cells. This also destroys the bone marrow’s ability to make new blood cells, so the patient is given healthy stem cells from a donor. With an allogeneic transplant, there is a chance of life-threatening side- effects because donor cells can attack your healthy tissues in a graft-versus-host effect. This option is therefore only suitable for a small number of patients, with very aggressive disease who are fit enough to be able to tolerate the treatment, because the risks associated with a stem cell transplant aren’t justified for patients with a slowly progressing disease like CLL. If this might be an option for you, then your haematologist will discuss it with you and give you a chance to ask questions. However, for most patients the risk of a transplant is greater than the benefit. There are now many alternatives to stem cell transplantation and the use of this approach is decreasing with the introduction of all the new agents.

Radiotherapy

This treatment uses high-energy rays, usually x-rays, to destroy the cancer cells. Radiotherapy is a usually given using a large external machine that directs beams of radiation at the cancer. Most patients with CLL don’t get treated with radiotherapy. However, if your spleen or specific groups of lymph nodes are particularly swollen or symptomatic, radiation may help shrink them. The procedure itself is painless, but common side effects of radiation therapy may include redness in the treated area, fatigue, nausea, and vomiting.

Splenectomy

On very rare occasions, selected patients have an operation to remove the spleen (splenectomy). CLL can cause the spleen to become very large, so that it presses on nearby organs and causes discomfort or pain. Surgery to remove the spleen may be an option if radiotherapy and chemotherapy fail to reduce its size. Your spleen may be removed by keyhole (laparoscopic) surgery or by a cut made just under your ribs in the middle or left side of your abdomen (open surgery). People tend to live a full life without a spleen, however, risk of infection increases. Splenectomy may also be required if the standard treatments for Auto- Immune Haemolytic Anaemia are inadequate.

Initial treatment

If you begin to suffer from symptoms, or if your lymph glands cause problems or the normal blood counts start to fall, you may need to start treatment. The very first treatment you have is called initial, or first-line, treatment. There are many different first- line treatment options for CLL patients. The choice of treatment will depend on the stage of your disease, your age and general fitness, as well as on whether you carry two prognostic genetic mutations, del17p or TP53. The most common first-line options are:

Chemo-immunotherapy

Fludarabine, cyclophosphamide and rituximab (often abbreviated to FCR). Over 90% of patients respond to FCR treatment with the benefit lasting an average of 5 years but 20% of patients still don’t require treatment at 10 years. Alternative first-line options for patients who cannot have Fludarabine include:

  • Bendamustine with rituximab
  • Chlorambucil with Obinutuzumab, rituximab or Ofatumumab
  • Ibrutinib for elderly patients with co-morbidities
  • Clinical trials can also be offered

Targeted therapy

BCR and BCL-2 inhibitors are an initial treatment option for adult patients with a 17p deletion or TP53 mutation as chemo- immunotherapy is not suitable for this group of patients. Options include:

  • Ibrutinib
  • Idelalisib in combination with rituximab
  • Venetoclax

Second-line treatment

Some patients may be refractory to initial treatment or experience a relapse. Refractory CLL occurs when the cancer has not responded to first-line treatment. A relapse is a return of the disease after a period of time following treatment without any symptoms or sign of the disease. The majority of treatment-responsive patients do eventually relapse.

Most patients with relapsed or refractory CLL will need second- line therapy (treatment other than the type used the first time around).

Second-line drug regimens may include:

  • FCR
  • Bendamustine with rituximab
  • Chlorambucil with a monoclonal antibody if the patient only received Chloranbucil on its own as first line therapy
  • Ibrutinib
  • Venetoclax
  • Idelalisib in combination with rituximab when the disease has been treated but relapsed within 24 months