Generality
The treatment of chronic myeloid leukemia (CML) includes several therapeutic options, able to keep the disease under control for prolonged periods of time. Performing routine analyzes on blood and bone marrow, and frequent evaluation of a hematologist or oncologist specialist, allow to monitor the progression of the neoplasm.
From the results of medical investigations (blood count, cytogenetic and molecular tests) it is possible to understand:
- The degree of treatment efficacy over time and the evolution of therapy response;
- If the disease is no longer responsive to drugs (resistance to therapy).
Monitoring and response to therapy
The correct monitoring of the course of the pathology is fundamental to verify the effectiveness of the therapy and to be able, consequently, to intervene promptly in case of failure of the cure.
The cytogenetic analysis and the molecular biology investigations are used, in addition to diagnostic purposes, also to assess the degree of response to the therapeutic protocol and to highlight the possible persistence of disease after treatment ( study of the minimal residual disease ):
- Complete hematologic response : when therapy begins to produce an effect, the number of leukemic cells is reduced. Haematological tests are no longer able to detect aberrant clones, but this is possible with cytogenetic analysis.
- Complete Cytogenetic Response : is obtained when the presence of the Philadelphia chromosome (Ph) is no longer detected by conventional cytogenetic analysis (standard approach to monitor the response to treatment) or with in situ fluorescent hybridization (FISH), a technique that evaluates the percentage of Ph + bone marrow cells. The cytogenetic analysis, performed on aspirated bone marrow specimen, is also the only method to determine the presence of any chromosomal alterations, additional to the Philadelphia chromosome, with a prognostic role.
- Complete Molecular Response : is reached when molecular analysis is unable to detect the expression of the BCR / ABL hybrid gene. Therapy has proved effective and the molecular signals that promote the production of bcr-abl proteins are so low that they cannot be detected even with highly sensitive molecular tests. Increased levels of transcription, which are being monitored, may indicate loss of response to treatment.
The achievement of these results is a very important result: many studies show that patients, with complete cytogenetic and molecular response, have a very high probability of surviving for a long time, without progressing to the accelerated and / or blast phase.
Many factors can influence the effectiveness of the therapy and for this reason, in the initial stages, it is advisable to proceed with tests after 3, 6, 12 and 18 months.
The information obtained so far from the clinical studies, which define the optimal response and failure at different times of the therapy, led to the formulation of a monitoring scheme, which must be followed for the correct management of the patient (indications proposed by European Leukemia-Net ):
| Time elapsed since the start of treatment | Fundamental steps of the optimal response to therapy | Investigations to be carried out |
| 3 months | Complete hematologic response : the number of white blood cells and platelets normalizes, blasts are not detected and the spleen is of normal size. | CBC |
| Minor cytogenetic response : the% of Philadelphia + chromosome-bearing cells drops to 65%. | Conventional cytogenetic analysis and FISH | |
| 6 months | Increased cytogenetic response : the% of Philadelphia + chromosome cells is less than 35%. | Conventional cytogenetic analysis and FISH |
| 12 months | Complete cytogenetic response : no Philadelphia + cells are detected in the blood or bone marrow. | Conventional cytogenetic analysis and FISH |
| 18 months | Complete molecular response : PCR investigations are very low levels of BCR / ABL genes. | Quantitative molecular analysis on peripheral blood (PCR) |
The hematologist (or oncologist) will be able to establish some goals and verify the effectiveness of the therapy in the specific clinical case, as patients react differently to the therapy and not everyone can reach the optimal therapeutic milestones within the expected time period .
Therapeutic options
The main goal of treatment for CML is to achieve complete molecular remission : the disease is controlled by treatment (even if it does not disappear completely) and the number of pathological clones produced is sufficiently limited not to cause any symptoms. Although it is not possible for most people to completely eliminate leukemia cells, treatment can help achieve long-term remission of the disease.
Therapeutic goals may include:
- Limit the manifestation of symptoms of chronic myeloid leukemia;
- Restore normal blood cell count parameters;
- Reduce the number of positive leukemia cells for the Philadelphia chromosome (Ph +) and the molecular signals (BCR / ABL transcripts);
- Aim for the disappearance of the Philadelphia + chromosomes (complete cytogenetic response).
Conventional antiblastic drugs
Some antiblastic drugs, such as busulfan (alkylating agent) and hydroxyurea (specific inhibitor of DNA synthesis), have been used, especially in the past, to achieve cytoreduction and control of the disease in the chronic phase. Conventional treatment has led to an improvement in the quality of life, but has not been able to significantly change the natural history of the disease, nor to prevent its progression to the accelerated / blast phase.
Recombinant interferon-alpha
Since the early 1980s, the introduction into the clinical practice of interferons has allowed us to observe, in addition to the reduction and normalization of the granulocyte quota, the achievement of the negativization of cytogenetic and molecular tests, inducing a greater duration of the chronic phase, with a consequent reduction of evolution in accelerated and / or blast phase. The interferon-alpha has reduced the role of conventional CML therapy: this drug is able to induce a complete cytogenetic response in 20-30% of patients, specifically interfering with the translation of proliferative signals in Ph + cells and inhibiting the multiplication of tumor progenitor cells. The interferon-alpha also acts with an indirect mechanism on the survival of leukemic cells, decreasing their cell adhesion and amplifying the activity of the cells of the immune system.
A limitation to the use of this drug is given by its non-negligible toxicity. Interferon side effects include fatigue, fever and weight loss. In order to improve the results achieved, interferon has been associated with other cytotoxic agents. Only the association of interferon with cytosine arabinoside ( ARA-C ) has been shown to offer better results than interferon alone, but without an obvious survival advantage.
Allogeneic bone marrow transplantation
The transplantation of stem cells from a healthy donor compatible with the recipient (allogeneic transplant) has represented for years the most frequent therapeutic indication and still today is the only treatment able to definitively eradicate the neoplasm.
This procedure, if performed in the chronic phase, can allow a five-year disease-free survival in about 50% of cases.
Allogeneic bone marrow transplantation involves a first phase of destruction of all (or almost all) Ph + cells through a conditioning therapy (chemotherapy in combination with total body irradiation), followed by the reconstitution of the haematopoietic marrow by the infused donor stem cells . Furthermore, the lymphocytes of the donor marrow contribute to controlling and / or eliminating any Ph + cells with an immune-mediated effect called " graft versus leukemia reaction " ( graft versus leukemia ). The response to therapy can be monitored by evaluating the disappearance or not of the molecular alterations typical of chronic myeloid leukemia. The allogeneic marrow transplant represents the therapeutic treatment able to "heal" CML, but unfortunately it involves a share of failures due to fatal and / or recurrent toxicity. This procedure, in fact, is very demanding and can be influenced by the age of the patient and the earliness of the transplant (months or years after the diagnosis of chronic phase): due to its potential danger, it is practicable only in patients under the age of 55 years, without further concomitant pathologies. Allogeneic transplantation is therefore a real therapeutic opportunity only for a minority of CML patients (also considering the difficulties of finding a compatible stem cell donor).
More recently, autotransplantation has been proposed in subjects with chronic myeloid leukemia not eligible for allograft (age, lack of donor, waste, etc.). The patient's bone marrow, reinfused after adequate intentionally cytocidal therapy for Ph + cells (with antiblastic + interferon), would reconstitute with a prevailing re-expansion of Ph- cells.
Imatinib mesylate (Glivec ®)
The history of the treatment of chronic myeloid leukemia has been revolutionized by the introduction of the first tyrosine kinase inhibitor (Imatinib mesylate), which has contributed greatly to improving patients' quality of life.
Imatinib is a specific inhibitor of BCR / ABL, designed after understanding the molecular biology of the disease and used in the treatment of chronic Ph + leukemia.
The drug is able to induce complete molecular cytogenetic remission in 80-90% of patients and is also active in myeloid neoplasms with eosinophilia and PDGRF involvement (platelet-derived growth factor, serum mitogen involved in many disease states, which promotes chemotaxis and proliferative capacity).
Imatinib selectively blocks the BCR / ABL tyrosine kinase activity by an ATP inhibitory mechanism: the drug binds the high-energy molecule (ATP) available in the specific domain of the BCR / ABL kinase, preventing the phosphorylation of other substrates and blocking the cascade of reactions that would be responsible for the generation process of Ph + leukemic clones. The dose used of this molecule (imatinib methysilate) varies from 400 mg / day to 800 mg / day in relation to the phase of the disease and to the response. Currently, it is the drug of first choice for the treatment of CML because of its remarkable efficacy. The side effects, reversible with the suspension and / or reduction of the dose, may be different (increased transaminases, nausea, skin rashes, fluid retention etc.).
Cases of drug resistance have been observed over time (for example patients with advanced disease) and biological-clinical criteria have been identified to define the type of treatment response. The mechanisms responsible for this resistance appear to be multiple (mutations in the kinase domain, amplification / over-expression of BCR / ABL, clonal evolution ...). In these cases continuing therapy with Imatinib is no longer appropriate.
For patients in these conditions the possible options are:
- Allogeneic transplantation;
- Conventional therapy (hydroxyurea, busulfan, etc.);
- Interferon;
- Experimental therapy (with 2nd generation tyrosine kinase inhibitors).
2nd generation tyrosine kinase inhibitors
Failure of Imatinib therapy is associated with the progression of chronic myeloid leukemia in accelerated and / or blast phase and results in a particularly negative prognosis. In recent years, pharmacological research has enabled the use, in clinical practice, of second-generation tyrosine kinase inhibitors, active in patients who have developed resistance to Imatinib: Dasatinib (Sprycel ®) and Nilotinib (Tasigna ®) are used in patients with CML in chronic phase and / or in progression refractory to Glivec ® and are able to re-induce complete and persistent haematological, cytogenetic and molecular responses. However, numerous studies have shown that the Ph + clone - due to its genetic instability - can develop mutations in the BCR / ABL kinase domain and prove resistant to different inhibitory drugs. Other molecules in experimental phase ( 3rd generation inhibitors ) are targeted to specific targets of chronic myeloid leukemia; in particular, they are able to sensitize Ph + leukemic cells that have specific mutations (example: Mk-0457 for resistant CML and with T315I mutation, which directly affects the binding site with Imatinib).
