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Why Choose Treatment for ALL in Israel?
Israel offers world-class leukemia care, particularly in private clinics located in Tel Aviv and the central region. Patients benefit from experienced hematologists, advanced diagnostic tools, and access to innovative therapies such as MRD testing and CAR-T cell treatment.
Acute Lymphoblastic Leukemia (ALL) treatment in Israel
Introduction
Acute Lymphoblastic Leukemia (ALL) is a malignant disease characterized by increased production and excessive accumulation of young lymphoid cells – lymphoblasts, of B or T cell origin. The cells gradually fill the bone marrow, and at some point also enter the peripheral blood. The accumulation of these cells in the bone marrow causes severe damage to the production of normal blood cells of all lines (white cells, red cells and platelets) and general symptoms. The current review will focus more on ALL in adults.
Epidemiology
The incidence rate of the disease in the United States is 1.5 per 100,000. The peak ages of the disease are 2-5 and after age 50. The disease is more common in white, wealthy and urban populations.
Etiology
The etiology of the disease is unknown. Clues to a genetic predisposition can be found in case reports of simultaneous development of the disease in identical twins and in the fact that the disease is more common in those with genetic syndromes, such as Down, Klinefelter, and Fanconi. Early exposure to radiation or chemicals has been found to be a possible cause of the disease. Specific subtypes of the disease are associated with viral infections, such as EBV (Epstein-Barr Virus) and HTLV1 (Human T-Lymphotropic Virus 1).
Clinical
The proliferation of cells in the bone marrow impairs its normal function. As a result, the patient will often present with neutropenia, which exposes him to various infections, including opportunistic ones. Anemia will cause weakness, dizziness, and shortness of breath with mild exertion. Thrombocytopenia will lead to a tendency to bleed. In addition, systemic symptoms may appear, such as bone pain, fever, sweating, and weight loss. Sometimes there is involvement of lymphatic organs, so the patient may present with enlarged lymph nodes or an enlarged liver/spleen. In about 10 percent of cases there is involvement of the central nervous system, which can manifest as a variety of symptoms, general or localized. In men, testicular involvement may occur. In the case of T-cell ALL, patients often present with a mediastinal mass that may cause difficulty breathing, pleural and pericardial effusions, and superior vena cava syndrome.
Classification of the Disease
In the 1970s, morphological classification dominated, dividing the disease into three groups (L1-3) according to the appearance of the lymphoblasts. Cytochemical staining helped to distinguish between acute myeloid leukemia (AML) and ALL. In the 1980s, lymphoblasts began to be classified into those of B-cell origin and those of T-cell origin, as well as according to their developmental stage. This classification is mainly based on the flow cytometry technique. This method allows the identification of various proteins located on the surface of the malignant cell or within its cytoplasm. B and T cells and each of their developmental stages have a specific protein composition. For example, CD19 appears on the surface of a B lymphocyte at a very early stage, while CD20 is added to the cell surface only at a later stage. In this way, lymphoblasts of the Pro B, Pre B, mature B type were divided, while those of the T type were divided into: Early T, cortical T, mature T.
In parallel with this classification, a classification based on cytogenetic or molecular abnormalities developed. This method is increasingly sophisticated and is becoming more important than its predecessors. Its importance is not only in its ability to predict a patient’s prognosis and possibly cause a change in the aggressiveness of the treatment given to him, but also in that certain abnormalities can constitute a specific therapeutic target. This was the case with one of the first subgroups discovered: patients with the Philadelphia chromosome (in a karyotype test) or the 9,22 translocation (in a FISH – Fluorescence In Situ Hybridization test) or the presence of the BCR/ABL1 gene (in a PCR – Polymerase Chain Reaction test). This disorder appears in up to 40 percent of ALL patients in adulthood. It is much rarer in childhood, and patients who carry it have a particularly poor prognosis. It later turned out that this disorder can actually be an effective therapeutic target, and this will be expanded on later. There are additional cytogenetic disorders in ALL patients, including various translocations, the absence of parts of chromosomes, and the presence or absence of entire chromosomes in the malignant cell.
Prognostic factors
Prognostic factors can be divided into those that become apparent around the time of diagnosis and those related to the degree of response. Older age and a high white blood cell count at diagnosis were discovered years ago as poor prognostic factors in ALL and remain so today. Not only do adults have a worse prognosis than children, but with increasing age – the prognosis becomes worse. A high white blood cell count is usually defined, somewhat arbitrarily, as above 30×10^9 in ALL of B-cell origin and above 100X10^9 in ALL of T-cell origin. Cell characterization remains important today, from a prognostic perspective, especially with regard to ALL of T-cell origin. The subgroup known as Cortical T ALL carries a better prognosis than the other types. In B-ALL, there are studies that indicate that the presence of the CD20 protein on the cell surface is a poor prognostic marker. From a cytogenetic/molecular perspective, we have already described the translocation (9,22) as ‘bad’, but so are translocations (4,11), (8,14) and the presence of a complex karyotype. A hyperdiploid karyotype, on the other hand, is considered to be a harbinger of a good prognosis.
Cutting-edge genomic diagnostics (NGS, MRD)
The formal definition of complete remission after treatment for ALL is normalization of blood counts and the presence of less than 5 percent blasts in the bone marrow. This definition is crude and relies on the fact that a small number of blasts can also be found in healthy bone marrow. With the advancement of technology and research, various methods have been found to assess response to treatment more delicately and accurately. These methods are called “Minimal Residual Disease (MRD) assessment methods.” The various techniques include the use of PCR, flow cytometry, and, in research, even gene sequencing. Each method has advantages and disadvantages in terms of its resolution, its suitability for all subtypes of ALL, the ability to use universal aids versus the need to develop patient-specific ones, the length of time until a response is issued, and the ability to cope with changes that have occurred in the leukemia cells. Various studies, mainly those dealing with the treatment of children, have shown that MRD testing, at times such as day 11 or day 24 after the start of induction therapy (there are studies with other schedules for performing the test), predicts to a high degree the expected prognosis for the patient. The use of MRD for the purpose of predicting prognosis and making therapeutic decisions has become the accepted standard of care worldwide in the treatment of children suffering from ALL. In the treatment of adults with ALL or other hematological malignancies, the use of In MRD it is still considered research.
Treatment
The classical treatments for ALL can be divided into two types of protocols:
- “BFM (Berlin-Frankfurt-Munster) model”: This model was historically developed for the treatment of pediatric ALL. Protocols such as those of CALGB (Cancer and Leukemia Group B), GMALL (German Multicenter Study Group for Adult ALL), ECOG (Eastern Cooperative Oncology Group) operate on this method. These protocols have two phases of induction therapy. The first is based on vincristine sulphate, prednisone, adriamycin and L-asparaginase. The second is based on a combination of cyclophosphamide (Cyclophosphamide, Endoxan), ARA-C (Cytrabone HCL, Cytarabine) and 6MP (Puri-Nethol, 6-Mercaptopurine). Further treatment includes consolidation therapies containing multiple drugs, late “re-induction” therapy, and maintenance therapy. Throughout the process, asparaginase is used
- Hyper-CVAD: This protocol has two parts that are given intermittently. It is much more toxic to the bone marrow, does not include asparaginase, and 6MP is included only in the maintenance phase. In both models, after entering remission, a decision must be made whether the patient is sent for allogeneic bone marrow transplantation or continues with several months of aggressive treatment followed by prolonged maintenance therapy of about two years. The issue of sending patients for bone marrow transplantation after achieving a first remission is not always clear-cut. Patients who are considered high risk and for whom a suitable donor in the family is found will be sent for transplantation. Regarding patients at normal risk or those at high risk, but only with a potential donor outside the family, the issue is controversial.
Advantages of ALL Treatment in Israel
Philadelphia chromosome positive ALL (Ph-pos ALL) – As mentioned, these patients were considered for years to have the worst prognosis among ALL patients. This was reflected in lower rates of achieving complete remission, higher rates of disease recurrence after achieving remission, and shorter overall survival. With the discovery of drugs from the Tyrosine Kinase Inhibitors (TKIs) family, there was a revolution in the treatment of patients with chronic myeloid leukemia (CML) – a disease in which the translocation is also expressed (9,22). CML patients were stopped from being sent for allogeneic bone marrow transplantation, and instead they were treated with the drug Imatinib (Glivec, a TKI). Similarly, attempts have been made to treat Ph-pos ALL patients with these drugs. Studies have shown that the use of drugs from the TKI family in these patients can increase the number of patients who enter remission and who can be sent for allogeneic bone marrow transplantation. In patients who are not suitable for transplantation, whether because of their age and general medical condition or because they do not have a suitable donor, such treatment can significantly prolong their survival. Despite the enormous progress that has been made in the field, it is still not clear which drug from the TKI family is ideal for these patients and what is the most successful therapeutic combination that should be given with the TKI.
Philadelphia chromosome negative (Ph-neg ALL) ALL – the progress in this disease is related to the field of immunotherapy:
- Antibodies: On the surface of the lymphoblast there are various proteins that can be a target for treatment by antibodies. There are different types of antibodies:
- ‘Naked’ antibodies – antibodies that bind to a protein and signal the cell to undergo apoptosis. An example of such an antibody is Rituximab (Rituximab, Mabthera). This antibody binds to the CD20 protein on the surface of the lymphoblast (it is not present in very young lymphoblasts) and causes the cell to undergo apoptosis. This treatment has been proven effective for years and improves prognosis in almost all lymphomas of B-cell origin, and only recently has it been proven to be very effective in B-ALL patients whose CD20 is present in at least 20 percent of their lymphoblasts
- Immunoconjugates – Some antibodies are linked to a chemical drug, others are conjugated to a radioactive substance that releases local radiation, and some are linked to a toxin, usually of bacterial origin, that can damage the cells it penetrates. The therapeutic idea is to deliver the active substance directly to the leukemia cell, using an antibody to a protein found on the cell surface. An example of such an antibody is Inotuzumab ozogamicin, which binds to the CD22 protein on the surface of the lymphoblast, undergoes rapid internalization into the cell and activation of the conjugated chemotherapeutic agent (calicheamicin) within the lysosome. The active chemotherapeutic agent enters the cell nucleus and leads to apoptosis. This drug has been tested in advanced ALL patients and has demonstrated some but limited efficacy.
- BiTE antibodies – These are engineered antibodies that have two different variable regions that bind to the tumor cell on the one hand and to a T-lymphocyte on the other. The idea is to couple the leukemia cell to the patient’s normal T-cell and allow the latter to damage the leukemia cell and cause its death. The antibody of this type, with which there is currently the most experience, is Blinatumomab (Blincyto). This antibody binds to the CD19 protein on the surface of the leukemia cell, but also to the CD3 protein on the surface of the T cell. This antibody has shown incredible efficacy so far, with approximately 70 percent of patients with B-ALL treated with it entering complete remission or close to it. The high efficacy led to the drug’s relatively rapid approval by the US FDA (Food and Drug Administration).
- Chimeric Antigen Receptors (CARs): This unique technique is based on removing the patient’s own T cells and processing them to express a receptor specific to the patient’s tumor cells. When the cells are returned to the patient, they are able to recognize the tumor cells and kill them. CARs are proteins that have one region that can recognize an antigen on the surface of the leukemia cells (such as CD19) and another region that can activate the T cell. The use of this technology is still research-only, but initial trials have shown remarkable success. It should be noted that the last two techniques mentioned, BiTE antibodies and CARs, attempt to activate the patient’s natural immune system. In both cases, severe neurological side effects have been observed, probably related to uncontrolled cytokine release. Therefore, both drugs are initially administered under very controlled conditions, such as in an intensive care unit.
Summary
ALL is a malignant disease, much more common in children. The classification of the disease and risk factors are increasingly based on cytogenetic and/or molecular factors. These also have the potential to be a possible therapeutic target. The therapeutic targets rely on various techniques for assessing MRD. Drugs from the TKI family are changing the face of Ph-pos ALL. At the same time, new immunotherapies are entering the world of Ph-neg ALL treatment.
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