Many cancers are treated with an endpoint of removal of the primary tumor and metastases so that grossly and microscopically, the body is nearly free of tumor cells. In the case of blood cancers, however, the endpoint is different where a complete normalization of blood cell count is necessary to ensure that the body is free from cancer. In the case of chronic myeloid leukemia, we go a step further by ensuring what we call a “molecular remission”. In this case, the body is not only free of cancer cells, but also free of all genes related to the cancer itself. Therefore, the genetic defect responsible for the cancer is eliminated. This genetic defect is called the BCR/ABL fusion gene. To simplify things, chronic myeloid leukemia can be treated, but also cured.
The main obstacle in the treatment of chronic myeloid leukemia is the development of a blast crisis. The disease remains in the chronic stage for years before proceeding to an accelerated phase followed by a blast crisis with life-threatening consequences. Treatment aims to prevent the development of a blast crisis and to treat it if it occurs. The treatment of chronic stage CML yields excellent results with first-class drugs in most cases, but treatment during the accelerated phase or blast crisis yields worse results and second-class drugs or even stem cell transplantation are considered in such cases. Complete remission from CML is measured by the absence of Philadelphia chromosome or BCR/ABL gene by a test called a PCR or a polymerase chain reaction, which detects fragments of DNA.
Treatment options
Tyrosine kinase inhibitor (Imatinib)
The introduction of tyrosine kinases was revolutionary in the management of chronic myeloid leukemia since they act directly on the gene responsible for cancer -The BCR/ABL gene-. They also induce cells with this defect to undergo apoptosis or “suicide”, thus preventing them from dividing.
The results of treatment with Imatinib in chronic myeloid leukemia during the chronic stage are near perfect, with an average of 94% of patients responding to this therapeutic approach. The main challenge, however, is the treatment of patients during blast crisis since they tend to have a non-optimal response with imatinib as a primary therapy. It is also well tolerated by the majority of patients at its most commonly used dosage of 400mg/day. The main side effects of imatinib are swollen legs and eyes, diarrhea, anemia and rash.
Other tyrosine kinase inhibitors
The reason as to why blast crisis is resistant to imatinib is the development of gene resistance where the gene responsible for the cancer changes itself or “mutates” to overcome imatinib. It may also multiply at an incredible rate. Thus, new drugs were developed, the second-generation tyrosine kinase inhibitors. They include nilotinib, dasatinib and bosutinib, and their main advantage lies in that they treat most mutations or “resistances” to imatinib and being able to treat blast crises with a better efficacy than imatinib.
Their main disadvantages are the adverse effects. For instance, some patients develop pleural effusion -a buildup of fluid around the lungs- and pericardial effusion -a buildup of fluid around the heart-. In addition, resistance may also develop against those agents.
Omacetaxine
Omacitaxine belongs to a family of drugs called protein translation inhibitors, meaning that they stop the cell from replicating by preventing the formation of proteins formed from the defective DNA. It can be given in cases resistant to multiple tyrosine kinase inhibitors, but it has a bad profile of side effects including anemia, infections, and low platelet count in more than half of the patients receiving it, so it is considered as a last resort before stem cell transplantation.
Myelosuppression
Myelo means bone marrow, and myelosuppression is the process in which we intentionally suppress the bone marrow to decrease the white cell count below a certain value. Drugs used for this purpose include busulfan and hydroxyurea. This is by no means a cure, and the effect is temporary, but it can be life-saving in some cases where the white blood cell count is too high as in a blast crisis, which increases the viscosity of the blood and causes problems like breathlessness, heart attacks and priapism -a sustained penile erection that can potentially cause gangrene in the penis with severe pain-. A rapid reduction of white blood cell count is therefore necessary.
However, the main side effect of this process is that it is hardly controllable and the risk of going too far and causing severe suppression is always present.
Leukapheresis
Due to the risks of chemical myelosuppression, it is rapidly falling out of favor with many centers around the world resorting to a physical process to get rid of the excess white blood cells. The basic process includes separating cells from the blood using a special filter and returning the blood back into the body, much like a hemodialysis.
Bone marrow transplantation
Bone marrow transplantation is the process where the patient undergoes an ablation of his or her bone marrow, followed by implantation of a new one. It can be either harvested before the ablation (Autologous transplantation) or from a donor (Allogenic transplantation).
In chronic myeloid leukemia, it is usually preferred in case of failure of other treatment, including tyrosine kinase inhibitors, but a number of patients may benefit from an early transplantation, especially if they are young and in the presence of a compatible sibling. Bone marrow can be rejected due to a reaction of the body known as “graft versus host disease”, and there is a risk of mortality, but both of these side effects can be reduced by properly matching the bone marrow and the chance is much lower in the case of siblings. New advances are being carried out in this field which allow doctors to harvest healthy cells from the patient before ablating the bone marrow, but measures have to be taken to ensure that they don’t harvest a leukemic bone marrow.
Splenectomy
Splenectomy is the surgical removal of the spleen, and it can be performed in chronic myeloid leukemia if the spleen is enlarged, causing symptoms or complications. The spleen may be “infiltrated” by the white blood cells if their level is too high and may in turn develop a complication known as hypersplenism, in which the spleen is “eating” cells at an accelerated rate, causing anemia or low platelet count. Vaccination may be needed before the removal because splenectomized patients have a high risk of developing some types of bacterial infections, including meningitis.