Chronic lymphocytic leukemia is the most common form of leukemia in adults in most western societies, and is only lethal due to its complications. Therefore, its treatment is tailored according to its effects, balanced with the side effects of the drug in relation to the patient’s condition.
⇒ Some cases do not need treatment at all.
Although the term leukemia is scary, some chronic lymphocytic leukemia patients can live for a decade following their diagnosis. The mere diagnosis of CLL is not enough to initiate treatment, and the presence of other symptoms, complications or markers is necessary before the start of chemotherapy. Among all treatment options, only stem cell transplantation is curative, but we measure treatment efficacy by what we call a “complete response”, which is the absence of signs of the disease, namely: no enlargement of organs -spleen, liver, and lymph nodes-, and normal lab findings including a normal white blood cell count, red blood cell count and normal platelets.
Evidence of rapid progression is necessary before starting treatment. They include massive or progressive enlargement of the spleen, massive or progressive enlargement of the lymph nodes and a group of symptoms called B symptoms, which include a significant weight loss of more than 10% in the past 6 months, night sweats and fever. Another important marker of disease activity is the rapid increase of white blood cell count.
CLL treatment options
Chemotherapy
Chemotherapy is considered the first-line treatment of chronic lymphocytic leukemia with many drug classes used in combination to achieve optimal results. The overall idea of chemotherapy is to curb the rapid proliferation of the dysfunctional white blood cells, which are immature and immortal leading to the progressive rise of the number of white blood cells.
Chemotherapy regimens include drug classes like nucleoside analogues. These drugs act through disruption of cell division, either by direct action on enzymes involved in the process or through changes in the DNA itself. The DNA is the main code of the cell, used to divide and form proteins. Cancers are formed when such DNA is altered, and these alteration are passed to the next generation of cells through cellular division. When nucleoside analogues incorporate themselves into the DNA of cancer cells, they terminate such processes of division, resulting in cellular death.
Nucleoside analogues include fludarabine, cladribine and pentostatin. The gold standard in the treatment of chronic lymphocytic leukemia is fludarabine, and the most commonly used combination is fludarabine plus cyclophosphamide and rituximab. Other combinations include replacing the fludarabine in the previous regimen with pentostatin, or using the famous CVP regimen which includes cyclophosphamide, vincristine and prednisone.
Cyclophosphamide is the major component of many anti- cancer regimens, including leukemia, and it is an alkylating agent, which means that it acts by directly damaging the DNA of cells through a chemical process called alkylation. The main drawback is that although this process affects cancer cells more than normal cells because cancer cells proliferate at a much higher rate and are more susceptible to DNA damage, normal highly dividing cells like those lining our intestines, those in the testicles and ovaries and our skin cells are also affected, leading to side effects like hair loss, infertility, stomatitis, vomiting, and diarrhea.
Biologic agents
Chemotherapy, however, is not the only treatment option, and the rise of biologic therapy has opened new horizons in the management of multiple diseases, including autoimmune disease and cancers. The basic principle of such treatment is stimulating the immune system to act against cancer cells. This can theoretically be used by administering viruses or bacteria and using them as a stimulant for the immune system, but practically the main method of immunotherapy is through monoclonal antibodies. Monoclonal antibodies are antibodies directed towards a single antigen or protein.
To fully understand how can an antibody help you fight cancer, consider this: your body has an army called the immune system, capable to fight bacteria, viruses and any intruder. However, cancer is smart, and blocks itself from detection hiding in plain sight through mimicking normal cells. Your body can fight cancer but can’t see it clearly. Monoclonal antibodies serve to flag these abnormal cells and let your immune system do the rest. Other monoclonal antibodies directly kill cancer or even stop its replication. The potential of immunotherapy are limitless.
But what do monoclonal antibodies target? The answer is actually simple. While they replicate, cancers maintain a fragment of their mother cell, known as clusters of differentiation or CDs. Those clusters are used for the diagnosis of the type of leukemia, its origin and predict its outcome. Monoclonal antibodies are designed to target certain CDs, making them highly specific. Drugs of this family include rituximab, duvelisib and ibrutinib. Most immunotherapies are used in combination with chemotherapy to achieve best results and can be used as a second-line treatment after chemotherapies fail because, unfortunately, they are much more expensive and less effective than chemotherapy, especially if used alone.
The combination of chemotherapy with immunotherapy may not be tolerated by the elderly, which usually make up most patients of chronic lymphocytic leukemia. Instead, chlorambucil is used with rituximab in fragile patients who can’t tolerate conventional regimens.
Some biologic therapies are termed targeted therapy. Although terms may be interchangeable, the concept is still the same. Targeted therapy aims to target a specific molecule on cancer cells that is not present on normal cells, be it an enzyme, a surface protein or a DNA sequence. Advances in this type of therapy are being made on a daily basis as it promises better result and lesser side effects in comparison to traditional therapies.
Bone marrow transplantation
Despite advances in other treatment modalities, stem cell transplantation remains the only curative treatment for CLL. Since CLL patients tend to be of an older age compared to other types of leukemia, the option of using high-dose chemotherapy in resistant cases may be perilous because of their fragile state. Stem cell transplantation means that after “ablating” the old bone marrow cells, new healthy cells are transplanted and therefore the origin of the disease is removed. Generally, stem cell transplantation is of two types:
- Autologous: Which means that stem cells are harvested from the same person before ablating the bone marrow then re-implanted.
- Allogenic: Which means that the stem cells are harvested from another donor, either from the bone marrow or from the blood (peripheral stem cell transplantation).
In case of CLL, the only recommended option is allogenic since the autologous transplantation always carries the risk or collecting cells with leukemia and recurrence of the disease. The main drawback of allogenic stem cell transplantation is rejection since the body may identify the new bone marrow as foreign leading to graft rejection. To avoid this, high-dose chemotherapy and radiotherapy are administered before the transplantation to “paralyze” the patient’s immune system. Matching of the bone marrow is also necessary between the donor and the recipient, similar to any other organ transplantation. The possibility of autologous stem cell transplantation is still debated, and trials are being carried out.
Splenectomy
Surgery may be required in some cases when the spleen is hugely enlarged leading to manifestations collectively known as hypersplenism, which include anemia, increased risk of infections and bleeding tendency due to the spleen destroying blood elements.