From incurable disease to precise treatment! Looking back on 40 years of human struggle against AML disease

Two years ago, a doctor's diagnosis kicked off the battleBill is ill and very illHe had acute myeloid leukemia (AML)In his bone marrow, the mutant cells grew like weeds, and the normal blood cells were too pressed to lift their headsBill tried a bone marrow transplant, received numerous chemotherapy, but failed to beat the cancer cellsThe doctor told bill that there was nothing traditional treatment could doTo survive, he had to go to clinical trials< br / > this is like a miniature of the life of all AML patientsAs one of the most poorly researched malignant blood cancers in the past 40 years, suffering from this disease is tantamount to being sentenced to death in advance< br / >In 1827, people had an initial understanding of leukemiaIn the following 20 years, more similar cases were reported, which caused people's attention to the diseaseIn 1845, Professor Rudolf Virchow, known as the "father of modern pathology", saw the abnormality of the patient's blood directly under the microscope for the first time: in the normal people's blood, the colored "red blood cells" accounted for the vast majority; but in the blood of leukemia patients, there are a large number of colorless or white small spheres, so leukemia (leukemia) got its name< br / >According to the rate of deterioration, scientists have coined the words "acute leukemia" and "chronic leukemia"According to the source of the mutated blood cells, leukemia is divided into "myeloid leukemia" and "lymphocytic leukemia"In the following decades, scientists have carried out a more detailed classification and classification of leukemia, but understanding the classification will not help the treatment of leukemiaFor this kind of persistent disease, especially acute leukemia, people have never found an ideal treatmentLeukaemia is also considered as an incurable disease for a long time< br / > the birth of modern chemotherapy < br / > a great breakthrough in the field of leukemia treatment came from an accident at firstIn the 1950s, doctors found that supplementing patients with folic acid could restore their hematopoietic function< br / > this brings to mind leukemiaAs we mentioned earlier, in the blood of leukemia patients, a large number of colorless or white small spheres "squeeze out" the position of red blood cells, which looks like abnormal hematopoiesis! Is it possible to treat leukemia with folic acid supplementation for these patients? < br / > DrSidney Farber of Boston Children's hospital is determined to test the ideaHe recruited a group of children with acute leukemia and injected them with folic acidThen, an unfortunate accident happenedMore than half a century ago, the cause of the disease had not been found out, the rash use of drugs had the opposite effect - folic acid not only did not stop the development of leukemia, but accelerated the deterioration of leukemia< br / >So, in turn, the use of folic acid antagonists to inhibit the role of folic acid, is it possible to treat leukemia? This time, fortune smiled at himUsing a drug called aminopterin, DrFaber successfully alleviated the condition of leukemia, and for the first time, let people see the hope of treating leukemia< br / > at present, aminopterin is a kind of chemotherapy drugTherefore, doctor Faber is also known as "the father of modern chemotherapy" His discovery ushered in a new era of leukemia treatment < br / > from "golden therapy" to bone marrow transplantation < br / > although Dr Faber initially treated another type of leukemia, this did not prevent chemotherapy from bearing fruit in AML treatment Among them, a therapy called "7 + 3" stands out and is welcomed by a large number of doctors Specifically, this therapy consists of two types of chemotherapy drugs, one is cytarabine (used for 7 days), the other is daunorubicin (used for 3 days), so the "7 + 3" therapy is also named In the past 40 years, this chemotherapy method has been widely used in the treatment of AML In terms of effect, it can greatly reduce the mortality of patients in the early stage of diagnosis For young patients under the age of 30, this treatment can also achieve a very high overall cure rate After treatment, more than 60% of patients can survive for more than 10 years! Therefore, it is also called "golden therapy" for AML < br / > but gold therapy has its limitations Although high-intensity chemotherapy can effectively kill cancer cells, it will also bring serious side effects to patients A statistic shows that if the patient is over 75 years old, the death rate of the patient is as high as one third within 30 days of treatment! Therefore, this kind of therapy is not perfect < br / > in addition to chemotherapy, other scientists are looking for the hope of treating leukemia in other fields In the 1960s, scientists were inspired by the success of the first human kidney transplantation Scientists can't help but imagine: since organs can be transplanted, what about the hematopoietic cells produced by bone marrow? If we kill the malignant cancer cells first, and then transplant the normal hematopoietic cells into the patient's body, can't we make their blood return to normal and achieve the goal of curing the disease! < br / > Ca.garcia s [CC by-sa 3.0() < br / > Professor Edward Donnell Thomas, an American scientist, is the first person to put this idea into practice Unfortunately, his attempt was thwarted at the beginning, with only two of the first six patients to have a bone marrow transplant successfully completed and none of them survived 100 days In the following experiments, bone marrow transplantation did not develop as well as the theoretical assumption From 1969 to 1974, none of the 54 patients who received transplants survived for a long time Infection, rejection and coagulation abnormalities after transplantation may endanger patients' lives < br / > the success rate did not improve continuously, which made the mainstream view at that time regard bone marrow transplantation as a helpless act of leukemia treatment, and also let patients and doctors smell it But Professor Thomas did not give up Although all 54 trials ended in failure, six of them had completely disappeared for a short time, which left him with a glimmer of hope < br / > with the accumulation of clinical experience, doctors found that postoperative infection and rejection were the main reasons for the failure of the trial Therefore, they continued to improve the operation procedures of bone marrow transplantation and improve the operation environment and conditions For example: the patients after transplantation were placed in the sterile ward; the antithymocyte globulin obtained from horses was infused to inhibit the rejection reaction; the laboratory was moved into the advanced cancer research center at that time < br / > in just three years, the survival rate of patients with advanced acute leukemia who received transplantation has finally increased from 0 to 13%, which is the first step from scratch! Since then, the therapeutic effect of bone marrow transplantation on leukemia has gradually improved By the end of the 1970s, more than half of the patients who received bone marrow transplants had regained their health For AML patients with limited treatment, bone marrow transplantation has become the "ultimate solution" < br / > In practice, doctors often use chemotherapy or radiotherapy to remove cancer cells from patients But these methods "do not divide between ourselves and enemy", will cause a great burden on the body, not every patient can bear For patients whose cancer cells have not been cleaned, bone marrow transplantation can not help them In addition, even in today's mature treatment conditions, bone marrow transplantation is also a high-risk operation, there is a certain risk of surgical failure and postoperative recurrence < br / > the exploration of AML treatment has once again entered a dilemma < br / > as the "magic bullet" flashed by a meteor, < br / > few malignant diseases remain unchanged for many years, with the exception of AML In the following decades, chemotherapy and bone marrow transplantation were few choices for AML patients Poor tolerance and high recurrence rate were still the sword of DAMOS hanging on the head of AML patients In general, the 5-year survival rate of patients is only 27% If the patients are over 60 years old, the 5-year survival rate is less than 10%, which is despairing < br / > since the 1980s, with the rapid progress of molecular biology, scientists have made new discoveries in the exploration of the micro world They found a special protein, CD33, which only exists in myeloid leukemia cells, but not in healthy hematopoietic cells If a bullet is fired at the target of CD33 protein, it will not be "enemy or friend" under radiotherapy and chemotherapy, but can achieve the precise attack on leukemia cells < br / > ▲ molecular structure of Mylotarg (gemtuzumab ozogamicin) (photo source: ADCReview.com ）< br / > according to this idea, scientists continue to study and get the "magic bullet" Mylotarg, which kills AML cells It is an antibody coupling drug composed of anti-CD33 monoclonal antibody and kazimycin The former can combine with CD33 protein and play a role of localization; the latter is a cytotoxin with strong toxicity and play a role of bullet Early clinical trials showed that Mylotarg was more effective than its side effects In general, 30% of patients' blood cells can return to normal What's more, more than a quarter of the over-60s with very low 5-year survival benefit from Mylotarg < br / > in 2000, the FDA accelerated the approval of Mylotarg for the treatment of AML patients over 60 years old who had relapse for the first time For those who can't survive chemotherapy, this is undoubtedly good news! However, in the larger clinical trials after the launch, the magic of "magic bullet" is no longer so magical Data showed that Mylotarg combined with chemotherapy did not achieve a more significant effect than chemotherapy alone At the same time, its side effects also increased The plot took a turn for the worse, leaving Mylotarg out of the market 10 years after it was approved < br / > behind the scenes of the right medicine < br / > fortunately, scientists have never stopped exploring AML When the industry is in trouble, the progress of basic science makes people have a new understanding of disease treatment In 2008, scientists sequenced the gene of an AML patient, and compared it with the normal genome, they finally found 10 gene mutations that may be related to the formation and progress of AML It is worth mentioning that this is the first time for human to sequence cancer genome completely This pioneering work provides a new way for scientists to better find cancer genes and apply drugs to the specific cases < br / > since then, with the development of whole genome sequencing technology, researchers have found that in a larger number of samples, it is related to the progress of AML