Acute childhood leukemia
Leukemia translates into the replacement of normal blood cells in the bone marrow by cancer cells. Anemia, the decline of leukocytes and platelets are part of the symptoms of leukemia. There are several treatments, including chemotherapy.
Summary
Leukemia: Definition
Causes and Risk Factors
The symptoms of leukemia
Complications
Further reviews and analysis
Differential diagnosis
Leukemia: Treatments
Psychological consequences
Global Prognosis
Special cases
Childhood leukemias: New treatments, new hopes
Acute childhood leukemia
Leukemia: Definition
Leukemia is defined by a clonal proliferation (of a kind) of a precursor of the blood cells in the marrow. An international classification defines different cytological types according to the cell line in question: lymphoid line or myeloid line. These diseases are serious.
However, the therapeutic advances are spectacular. The first prolonged remissions date from the end of the years 1960. More recent advances are a better approach to care (generalization of the use of central catheters, wide use of potent antibiotics, better use of analgesics) and intensified chemotherapy ( Use of a treatment of intensification, better control of the allograft of Marrow. The understanding of leukemias has been greatly improved in recent years by molecular biology.
Acute leukemias are the most common childhood cancers, accounting for one-third of pediatric cancers, with an annual incidence of 1.5/100000. Acute leukemias are 20 times more frequent in children carrying a Down syndrome.
Leukemia translates into the replacement of normal blood cells in the bone marrow by cancer cells. These abnormal cells prevent on the one hand the marrow from making the normal cells and on the other hand will infiltrate the different organs.
Spontaneous evolution was rapidly fatal in tables of severe infections or large hemorrhages. Currently, modern therapies result in remission in more than 95% of cases of acute lymphoblastic leukemia.
Causes and Risk Factors
The application of molecular biology techniques to the areas of leukemia improves the understanding of these diseases. Recent work focuses on the early, molecular, and leukemogenesis events. From now on, these techniques improve the identification of the disease by allowing the definition of fusion transcript and the description of rearrangements between immunoglobulins genes or T receptors.
The inputs of these techniques are two orders: better knowledge on the molecular definition of the disease and possibility of a follow-up of the residual disease. The interest of the in vitro test techniques of the anti-leukemia activity of the various drugs should be reported. There is little work on the physiology of leukemic cells, with the exception of studies of angio-genetic factors.
In the vast majority of cases, the case or causes remain unknown. Infectious agents, probably viral, could be involved. Among the infectious causes the EBV virus is associated with Burkitt's lymphoma. Exposure to certain toxic substances (benzene, heavy metals), ionizing radiation or chemotherapy has been evoked as risk factors.
The symptoms of leukemia
Clinical signs reflect either medullary insufficiency or visceral infiltration by abnormal cells. Medullary insufficiency causes:
A decrease in red blood cells thus anemia: paleness, asthenia, slimming, alteration of the general condition;
A decrease in leukocytes therefore a fragility towards infections: dragging angina, unexplained fever...
A drop of platelets therefore a thrombocytopenia: Hemorrhages, Epistaxis, petechiae, purpura, bruises etc... Retinal hemorrhages visible at the bottom of the eye are anticipations of Cerebro-leptomeningeal hemorrhages.
The infiltration of organs by leukemic cells causes:
Increased liver and/or spleen volume
Increased volume of lymph nodes;
Bone or osteo-articular pain;
Abdominal pain
Hemorrhagic gum hypertrophy (gingivitis)
In the slightest doubt, the doctor uses the laboratory.
The NFS provides two types of information. Practiced early, at the "aleukemic" stage, cancer cells have not yet appeared in the bloodstream. Blood analysis doesn't show them. On the other hand, the medullary deficiency results in:
The fall in the number of red cells: anemia normochromic arégénérative;
The fall in the number of leukocytes: neutropenia;
The drop in the number of platelets: thrombocytopenia.
Later, it highlights the abnormal young cells (blasts) that have passed through the circulation. These results make it necessary to perform a marrow puncture in order to make a smear or myelogram.
Two main forms are distinguished:
Acute lymphoblastic or L.A.L. leukemias, the most frequent between 18 months and 16 years, are highly susceptible to modern treatments since complete remissions are reached in more than 95% of cases for many months.
Acute myéloblastiques or Heia leukemias mainly affecting children over the age of 12 and more severe
Complications
Before modern treatments, children with leukemia died quickly. Currently, various therapies developed in recent years allow for remissions of longer or shorter duration. We are talking about complete healing when a remission lasts 5 years. A "remission" is defined by the disappearance of clinical and hematologic signs with reappearance of normal medullary lines in the marrow. Several complications may occur:
Medullary Aplasia is caused by treatment that treats leukemia in some way, but causes serious infections or severe hemorrhages.
The various treatments have a immunosuppressive effect and make children very susceptible to viral infections (chickenpox, measles etc...)
Localized leukemic infiltration can reach the brain (meningitis leukemia). These leptomeningeal relapses were responsible for early hematologic relapses during the first year of treatment. Preventive treatment is currently being systematically carried out. Testicular damage is relatively frequent and imposes regular examination of the external genitalia (progressive and painless increase in the volume of a testicle).
When the disease no longer responds to maintenance or réinduction treatments, the evolution is towards death by Aplasia medullary most often.
Cytogenetic anomalies, Immunophénotypique profile, leukocytosis (white blood cell augmentation) are important prognostic factors.
Further reviews and analysis
Myelogram
This examination is essential to confirm the diagnosis and specify the exact cell type, which is fundamental for the treatment and prognosis. It is most often performed in children at the iliac ridges. The use of premedication allows to practice this gesture without inconvenience for the child. Cytological examination is used to confirm the diagnosis of leukemia by typically showing a massive infiltration of monomorphic cells. The FAB classification that defined the Lal at small lymphoblasts (LAL1) or large lymphoblasts (Lal 2) and the Lal 3 Oy lal type Burkitt is no longer used today.
The myelogram takes into account the appearance of lymphoblasts, the percentage of blastose of mitoses images (cell divisions), morphological peculiarities, and increased leukocyte types.
Several highly specialized exams are designed to characterize clonal proliferation:
Immunophénotype the identification of lymphocyte surface proteins, referred to by the initials CD (differentiation cluster), and a number allow to assign an identity to clonal proliferation. We can distinguish markers from the T line (CD 2, CD 3, CD 4, CD 5, CD 7, CD 8), Markers of Line B (CD 19, CD 20, CD 21, CD 21, CD 22, CD 23, CD 24, intra-cytoplasmic immunoglobulins, surface immunoglobulins), markers of the myeloid line (CD 13 , CD 14, CD 33), and undifferentiated medullary cell markers (CD 34, CD 10). About 15% of the Leukemias Express T markers and 85% of the B markers.
Cytogenetics malignant clones exhibit cytogenetic anomalies. Anomalies of chromosome number (Hypodiploïdie-45 CHR, or Hyperdiploidy + 46 CHR) and chromosome structure anomalies are described. The presence of the PH1 chromosome is a bad prognosis. To anomalies in who 2008, additional anomalies such as 12p deletion and 6q deletion are added.
Molecular biology two types of anomalies are described at the level of the genetic material of malignant clones. On the one hand, fusion transcripts corresponding to a fusion of 2 genes located on 2 different chromosomes, sometimes leading to a protein with function, most often interesting the regulation of the cell cycle. The BCR-ABL, MLL, TEL-AML 1 transcripts, respectively, for T (9; 22), T (4; 11) T (12, 21) translocations are described. On the other hand, within the clones of lymphoid cells, there is very frequently a rearrangement of the different genes encoding the Immonoglobines-lineage B-or the receptor T-lineage T.Il is possible to use the techniques of molecular biology either As a diagnostic aid, or to better appreciate the decrease in the number of cells during treatment. In this case, the interest of these techniques is to increase the sensitivity of the detection of residual clonal cells to thresholds close to 1/10 000 cells (2). However, in routine, these techniques are informative only for about 70% of patients.
Other biological anomalies above all, among the hyperleucocytaires forms, various anomalies may be present: disseminated intravascular coagulation, hyperuricemia, abnormalities of phosphocalcic metabolism (Hyperphosphorémie, hypo or Hypercalcemia). Renal failure may be present either by infiltration of the renal parenchyma or secondary to the hydroelectrolyte disorder (hyperuricemia, phosphocalcic metabolism disorders).
Differential diagnosis
Angina with lymph nodes, asthenia and splenomegaly simulating a enzootic can be in reality only infectious mononucleosis (MNI).
Osteo-articular pain can evoke acute rheumatic fever (febrile painful syndrome, accelerated sedimentation speed, etc.).
Purpura with platelet drop can translate idiopathic thrombocytopenia.
Some aspects to the NFS are misleading and require control.
Leukemia: Treatments
Central Catheters
Several types exist-simple percutaneous catheters, sleeves or chamber catheters-the choice of which is related to the practice of each team. They allow to administer cytostatic drugs in good safety conditions-especially without the risk of extravasation-and to carry out the monitoring levies without too much discomfort to the child. Their use requires rigorous asepsis conditions. They nevertheless expose the risk of infectious contamination, in particular to germs of Staphylococcus épidermidis types.
Chemotherapy by general means
Treatment is done in accordance with therapeutic protocols. The overall structures of the French protocols or Western countries are very similar today. They all have 4 stages: an initial period of intensive induction (corticosteroids, vincristine, asparginase and sometimes anthracyclines) for 3 to 4 weeks with Cerebro-meningeal prophylaxis (methotrexate), a consolidation treatment up to Complete remission, an intensification treatment that takes over the drugs used during induction to consolidate the remission and finally, maintenance treatment for 2 to 3 years to avoid the recurrence of the disease.
Each stage of treatment is crucial and requires regular monitoring and hematologic monitoring of the patient including myelogram and extension balance.
Chemotherapy drugs are very toxic, dangerous to handle and require a perfectly honed team, aware of complications, side effects and the necessary surveillance.
All these treatments lead to complications that must be prevented:
Infectious complications:
The precautions of asepsis must be draconian;
Treatment for fungal infections is systematic: Fungizone ®, Mycostatin ®..
Antibiotics are very much used;
The transfusion of leukocytes is a very significant recent technique;
Hemorrhagic complications:
All traumatic attacks should be avoided: intramuscular injections, arterial punctures, dental care etc.
Platelet transfusions are often performed;
Metabolic complications.
Management of chronic myeloid leukemias and positive Philadelphia chromosome lymphocytic Leukemias has changed dramatically since the years 2000 through the use of targeted therapy, imatinib (Gleevec ®) in these two types of Childhood leukemia. may be prescribed for first-line use, this drug is very effective and can be administered orally, with less than 1% serious side effects.
Antibiotic therapy
Children in leukemia treatments are exposed to infectious risk, either by the existence of chemotherapy-induced neutropenia or by the presence of prostheses as a central catheter. The existence of a fever is a circumstance which always requires to start as soon as possible an empirical polyvalent antibiotic without waiting for the determination of the responsible germ. The principles of the choice of antibiotic therapy are: initial antibiotic therapy effective against Gram-positive cocci and Gram-negative bacilli, including streptococci, Bacillus pyocyanique, and second-line antibiotic therapy (in case of Persistence of fever), active against fungal infections, including Candida and Aspergillus. Cytokines (G-CSF and GM-CSF) did not alter this strategy and are only indicated in the presence of an uncontrolled antibiotic infection.
Prophylaxis of NEUROMÉNINGÉES attacks
The irradiation of the brain to the second cerebral vertebra is systematic, in order to avoid a risk of very high secondary localization in this pathology. This prophylaxis gives the best results. The dose of 24 grays is effective but causes significant sequelae: endocrine disorders with pituitary failure, memory disorders... Lower doses: 18 grays or even 12 grays, seem equally effective, but significantly less toxic. It seems prudent not to administer this treatment for children under the age of four.
Other techniques are sometimes used. Intrathecal injection of cytostatic drugs is sometimes recommended: corticosteroids, methotrexate and Aracytine. Administered in sufficient numbers (+ 14), they appear to be capable of preventing meningeal harm by themselves. High-dose methotrexate is the only cytostatic to possess an antidote in the form of folinic acid. It is therefore possible to administer it at conventional doses or at large doses requiring very strict control of its neutralisation and elimination. These high doses allow to benefit from the meningeal passage of this drug which thus contributes to the prevention of secondary leptomeningeal locations.
Marrow grafts
Place of the Marrow allograft.
Except for the exceptional lymphoblastic leukemias appearing from a very severe prognosis-form of the infant, failure of induction, existence of a translation T (9; 22) t (4; 11)-The allograft of Marrow does not appear to be indicated during a first Outbreak of the disease.
On the other hand, this treatment is indicated for relapses. But even in these cases, the indication is carried individually, both according to the tolerance of previous treatments, the history of the disease-delay and sites of relapse-and the type of donors available (Geno-identical donors Intra-familial or unrelated donors, or even haplo-identical parents). The efficacy of Allograft is due both to the conditioning but also to the immunological effect of the graft-to-host reaction, which is responsible for a significant morbidity.
Place of the Autograft.
The Autograft is a low-toxicity procedure, the results of which are discussed. This procedure is applied in the first complete remission in case of formal indication of graft and in the absence of marrow donors, and in case of relapse.
Painkillers
The management of a malignant hemopathy requires the practice of painful therapeutic (intrathecal injection) or diagnostic (myélogrammes) gestures, not forgetting the physical pain of which the disease may be responsible. Perfectly codified procedures exist to limit pain: use of nitrous oxide, use of association of Hypnotics and analgesics.
Psychological consequences
The onset of a vital prognosis disease, requiring long-term treatment, is such as to profoundly alter the interactions of the family group to which the child belongs. It is important to ensure the dynamics of the relationships that are in such dramatic moments.
The child enters the hospital in a climate of anxiety and urgency. The often alarming somatic state increases the sense of fear. For some children, the aura that surrounds the diagnosis, more than the severity of their condition, helps to create this climate of terror that can be alleviated by the conditions of reception and support.
Before the age of 3 or 4, the child responds to the separation, pain and threats posed by the diagnostic and therapeutic means: it may present the signs of separation from Robertson. Sometimes he perceives that he is severely affected, feels that he needs to be cared for and remarkably accepts painful care.
The child aged 4 to 10 years, after the reaction to hospitalization phase, regresses; exhaustion, linked to illness and treatment, facilitates the acceptance of care. He often shows aggressive and regressive behaviour with his mother while the doctor or nurses weave close collaborations to fight the disease; This biparting of the relationship is often the source of clashes between mothers and caregivers. Often the child seems to defend themselves by identification with the aggressor: the Doctor. Very young, the child is interested in care, exams and uses ritualization.
Other children are unable to adapt and refuse everything that comes from the hospital. They live only on the basis of their output which they claim every time they see the doctor and are dependent only on their mother. The authors insist on the correctness of the child's judgement on the psychological discomfort and technical hesitations of the Medical Corps; This is probably a critical exacerbation triggered by anxiety. The child establishes a positive link with the service insofar as it is physically relieved and feels cared for effectively. Some children suffer, due to their illness or treatment, significant biological upheavals that cause a kind of slump, adding to their exhaustion a withdrawal, a disinterest in their bodies. These states differ from regression behaviors: inhibition of motor functions, anorexia, language rejection... etc.
For parents, the entry into a service specialized in leukemia can already impose the reality of the diagnosis, but also a hope in the increased therapeutic efficacy. In these centres, the start-up of treatment, contact with other severely affected children and some of them disappear over the course of the weeks is a trauma in which the mother feels at risk as does her child. This threat often translates into parents ' intellectual inhibition at a time when contact with the healthcare team is particularly important. Mothers need to be listened to, to express their anguish, their revolt, their denial, their fear. Then this first phase, the daily needs of the sick child impose a return to the real. Many parents then axent on the exams, the therapeutic rituals obsessionnalisant their existence. Others, more hysterical, suppress massively anguish or protect themselves by a very external dramatization. Fathers often have a feeling of helplessness that threatens their role as protector and their reactions of escape, anxiety or person-to-person can increase the climate of anguish of all.
During remissions, fear persists. Hopefully, we prepare for grief. The temptation to overprotect the child is difficult to overcome.
Nurses give many and difficult care. They bear the physical suffering, the anguish of the children and their families and attach themselves to the children while fearing this attachment.
Doctors and nurses, faced with the anguish of children and parents, live their personal problems and assume more or less well this painful relationship. Some doctors take an attitude of scientific research that gives them a necessary refuge, a justification for all these therapies, hoping to cure these children one day; Others unload their anxiety on a psychologist or a psychiatrist.
Global Prognosis
Any leukemia is spontaneously lethal, and only one treatment makes it possible to hope for a correction of this condition. With the current protocols a cure is observed in approximately 2/3 of the cases. The failures of these treatments decompose into toxic deaths-related to the consequences of treatment-in about 5 to 10% of cases, and in relapse. Although the answer to treatment is ultimately the only determinant, it is possible to describe many prognostic factors.
Among the unfavorable elements, one can cite: age (between 1 and 9 years), male sex, high levels of white blood cells, blasts, a normal hemoglobin figure, a low platelet count, a large liver and a large spleen, lymph nodes, the presence at Diagnosis of a meningeal, testicular attack, of a large mediastinum.
On the biological level, are poor prognosis of T markers, myeloid markers, the absence of CD 10, a low DNA index, cytogenetic anomalies (in particular translocations 9-22 and 4-11, Hypodiploïdie and chromosome Ph1).
Other adverse factors are corticorésistance (+ 1000/mm3 blasts at 7 ° Day of treatment with corticosteroids), a slow response to chemotherapy (Myelogram of J7, J14 or J21), a persistence of a residual disease after induction, a Wrong answer in vitro... These prognostic factors are closely related to each other. Only multivariate statistical analyses are used to determine the respective weight of the different prognostic factors. Through these multivariate analyses, the number of relevant prognostic factors is significantly simplified, and only 4 factors remain significant: age, leukocytosis, sex, and cytogenetics.
Special cases
Acute lymphoblastic leukemia (BURKITT TYPE)
This subtype of leukemia (formerly FAB: LAL3) corresponds to a proliferation of mature lymphocyte B cells expressing surface immunoglobulins. This proliferation is associated with several cytogenetic anomalies that are relevant to chromosome 8 and another chromosome: 2, 8, 14, or 22. At the molecular level, these cytogenetic anomalies correspond to a fusion transcript of the immunoglobulin genes (located on chromosomes 2, 8, 14 or 22) and the C-myc oncogene.
The symptoms appear much more brutal than in the other forms of common leukemia of the child. Gingival and neurological damage is common with cranial pairs. Treatment is similar in principle to that of Burkitt lymphomas. It consists of intensive cures for a period of 6 months without maintenance treatment. The results are good in nearly 90% of cases. The few relapses occur in the first year of treatment.
MYÉLOBLASTIQUES Acute leukemias
Acute myéloblastiques leukemias include 7 different subtypes. LAM 1 and 2 are common myéloblastiques acute leukemias. LAM3 is called Promyelocytic and has a cytogenetic characteristic T (15; 17) and a molecular anomaly (PML-RAR) characteristic as well as a very common association with a hemorrhagic syndrome. The LAM4 is called Myelo-monocytic and the monoblastic LAM5. LAM6, Erythro-leukemia, is a proliferation of erythroid precursors. LAM7 is a proliferation of mégacaryoblastes. The symptoms resemble those of acute lymphoblastic leukemias with subcutaneous tumors in the facial region.
The treatment combines repeated intensive chemotherapy treatments. The most useful medications in acute myéloblastiques leukemias are aracytine, VP16, antracyclines and their derivatives. Other medicines used: The Asparaginase, the Purinéthol, the 2 cda...
The total duration of treatment does not exceed 6 months and the interest of maintenance treatment seems low. Medullary transplantation, with an HLA-identical intrafamilial donor, provides a certain benefit. If it is not feasible, the autograft or a marrow transplant with an unrelated donor is not useful in the first remission but is useful in case of relapse.
The treatment of LAM3 is based today on the effect of retinoic acid, derived from vitamin A. This is the only example in oncology where treatment is not intended to reduce the number of pathological cells, but to give them the opportunity to resume interrupted maturation. However, if retinoic acid alone is capable of inducing a complete remission, it is not able to maintain this result and requires to be associated with cytotoxic treatments. The treatment of LAM7 is also peculiar. Associated very often with Down syndrome, its treatment can be limited to small doses of Aracytine..
The overall prognosis of acute myéloblastiques leukemias is still poor with a recovery without recurrence of 50%. In recent years, targeted therapies (monoclonal antibodies) have appeared and represent a hope for the prognosis of these patients.
Childhood leukemias: New treatments, new hopes
Currently, several new treatments are being developed in different countries.
For example, in the United States, an advisory group of U.S. health Authorities (FDA) recently recommended the approval of the first treatment to genetically modify a patient's immune system to combat leukemia. Developed by Novartis, this géniqueest therapy developed from the own T lymphocytes of patients ("killer" lymphocytes), cells of the immune system. They are collected and then genetically modified in order to be able to selectively attack cancer cells. Researchers are also programming these lymphocytes to accelerate their multiplication.
Once the T lymphocytes have been taken to be reprogrammed, the patient is treated with chemotherapy and then reinjected his own modified immune cells, which will hunt down and potentially destroy the cancer cells. We are talking about personalized immunotherapy, also known as CTL019.
In addition, the Janssen-Cilag laboratory has developed a targeted therapy, ibrutinib (Imbruvica ®), a molecule which obtained its marketing authorisation in France in February 2017 in the treatment of chronic lymphoid leukemia (LLC) in Therapy in patients who have not received prior treatment. However this treatment is indicated in the adult only for now.
Finally, the National Cancer Institute offers different experimental protocols using different treatments. These treatments are accessible with the prior signature of informed consent. The aim is to enrich the basis of therapeutic possibilities and, in the long run, to obtain MDA for protocols which prove to be effective.
0 comments:
Post a Comment