A cocktail of drugs to counteract one of the most difficult pathologies to fight: amyloidosis, which attacks the organs one by one, especially the heart, liver and kidneys. Now, thanks to the combination of drugs identified as a possible therapy against the disease, the goal of winning it becomes more and more concrete. They have been published in the international journal New England Journal of Medicine the results of the international clinical trial of the combination of daratumumab, cyclophosphamide, bortezomib and dexamethasone in light chain amyloidosis (AL amyloidosis) .The study was coordinated by Professor Giampaolo Merlini, founder of the Amyloidosis Center of the San Matteo Polyclinic in Pavia, and has involved more than 300 patients, in North and South America, in Europe, the Middle East and Australia.
The results led Fda (Food and drug administration, the US government body that deals with the regulation of food and pharmaceutical products) and Ema (European Medicines Agency) to approve daratumumab in the treatment of patients with this rare disease. for which up to now there were no therapies with specific indications.
The clinical trial was largely based on the work carried out over the years by the Pavia Center and in particular on the research of Professor Giovanni Palladini, a student of Merlini and current director of the Center, who developed the criteria for evaluating the efficacy of therapy in patients with AL amyloidosis.
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“Daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone is effective in 90% of patients with AL amyloidosis, is well tolerated and doubles the probability that it will be possible to improve the function of the organs affected by this fearful disease – explains Merlini – and will become a new standard of care for patients with AL amyloidosis “.
Thirty types of amyloidosis
Amyloidosis is a group of diseases that affect various organs and systems. They result in a huge accumulation of proteins in our body to form fibrils. The latter, accumulating in the tissues and organs, give rise to a dysfunction, since these are also important organs: brain, heart, liver and the whole peripheral nervous system. Organs that are compromised, so as to generate a more or less serious picture of these diseases. 30 different types of amyloidosis have been recognized, each characterized by a different production of abnormal proteins. All these proteins, however, are characterized by the Congo red color. In fact, in order to be able to identify with certainty the amyloid substance in a cytological or histological sample it is necessary to subject the preparations to this staining: while with the common routine staining the amyloid substance appears amorphous, fibrillar and pink, after treatment with Congo red. turns bright red. Some types of amyloidosis are inherited. And among these the most frequent is the amyloidosis due to accumulation from transiletine. But the most commonly encountered is AL amyloidosis.
The most common form
AL amyloidosis is the most common form and most often affects the heart (in 75% of patients), the kidneys (in 65% of cases), the liver (20%) and the nerves that transmit sensitivity from the feet and hands and those that regulate blood pressure (20%). It often involves more than one organ in the same patient. In AL amyloidosis, amyloid deposits are formed by fragments of antibodies, the light chains, produced by cells found in the bone marrow, called plasma cells. Daratumumab is a monoclonal antibody that selectively affects plasma cells causing their death. Combined with therapy that includes a proteasome inhibitor, such as bortezomib, it accelerates the response and deepens it, facilitating the rapid recovery of the function of the affected organs.
Research
This result is added to the many achievements of the San Matteo Amyloidosis Center whose researchers, over the years, have discovered new types of amyloidosis, developed more reliable diagnostic procedures, new methods to predict prognosis and to evaluate the response. to therapy, in addition to having experimented with increasingly powerful drugs and therapeutic schemes. The Center for Amyloidosis of Pavia is an international reference center for systemic amyloidosis and can make available to patients all the technologies and tools to diagnose and follow these very complex diseases. Approximately 4,000 evaluations of patients with amyloidosis are performed each year and clinical activity is closely combined with laboratory research projects and clinical trials.
But what are the symptoms that should alert us? “Initially they are subtle, because the pathology begins in a silent and creeping way, slowly affecting tissues and organs that are involved – explain the researchers -. Therefore, if there is greater cardiac involvement, dyspnoea will arise, the appearance of peripheral edema, with consequent sensation of shortness of breath, asthenia, muscle weakness. In other cases, however, the involvement is neurological, and therefore symptoms related to neuropathy will appear: paraesthesia, sensations of cold, lack of strength in the lower limbs, weight loss, fever all very generic and variable symptoms that also depend on the type of amyloidosis and the type of organ involved. In addition, renal failure can also arise with the presence of foam and protein in the urine “.
The exams to do
What tests should be done if amyloidosis is suspected? We need to research if there are any haematological alterations, in the case of AL alteration, or investigate if there is a genetic type, in particular in transyletin amyloidosis. Then there are specific tests: immunofixation in serum and urine, dosage of free light chains in serum, some parameters of cardiac biomarkers such as Pro Bnt and Tropoin index of cardiological damage, index of renal function, that is all that is needed for the diagnosis of kidney diseases: azotemia, creatinine, urinalysis and 24-hour proteinuria to understand which organ is most involved. In the neurological forms, electromyography is required, which serves to understand exactly what type of pathology is in progress.
Against amyloidosis there are 62 centers that operate in Italy, a network that collaborates as a reference center for rare diseases, i.e. diseases that are not very frequent but which do not have such a low incidence, if we calculate that the cases treated are about 800 per year. Furthermore, in the Lazio region there is a register dedicated to these diseases. “The reason for the exchange lies in the fact that each center is specialized in the neurological sector rather than in the cardiology sector – explain the hospitals of the network -. In addition, the important thing is that all apply shared therapeutic protocols for the benefit of patients”.
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