Dr. Eloise Beggiato (Turin): “Despite the progress made in the therapeutic field, the possible complications due to the disease should never be underestimated”
Before 2007, when the first complement inhibitor, eculizumab, was approved for the treatment ofparoxysmal nocturnal hemoglobinuria (PNH), about 35% of people affected by this rare blood disorder died five years after diagnosis. The advent of this category of drugs has radically changed the natural history of PNH, e.g today patients have a life expectancy comparable to that of the general population. “Despite these enormous achievements, paroxysmal nocturnal hemoglobinuria remains a complex and subtle diseasewhich should not be underestimated and which must be constantly monitored to avoid complications”, states the Dr. Eloise BeggiatoMedical Director of the Hematology Unit of the Molinette Hospital in Turin.
A DISEASE THAT BEHAVIORS LIKE A TUMOUR
L’paroxysmal nocturnal hemoglobinuria (PNH) it’s a rare hematopoietic stem cell disease, the cells which, upon maturation, give rise to the various components of the blood, i.e. red blood cells, white blood cells and platelets. It is characterized by episodes of hemolysis (premature destruction of red blood cells) which may be associated with hemoglobinuria (presence of hemoglobin in the urine), with consequent thrombotic manifestations, cytopenia and bone marrow failure. It is a ‘clonal’ hematological disease. This adjective indicates the abnormal growth of a defective cell population starting from a single stem cell: it is not a tumor pathology, but in fact it behaves as if it were one.
“Sometimes there are patients who present a concomitant picture of bone marrow aplasia or myelodysplasia or who, later, actually develop some neoplastic form, such as leukemia,” explains Dr. Beggiato. “Despite some similar characteristics, however, PNH should not be confused with hematological malignancies.” Paroxysmal nocturnal hemoglobinuria, in fact, is due to an acquired somatic mutation of a single gene, CALLwhich affects one or more hematopoietic stem cells. This genetic defect leads to the lack of synthesis of some membrane proteins, in particular CD55 and CD59, essential in defending the cell from the lytic action of complement, the innate defense system of our organism.
A LONG-TERM THERAPY
Precisely because of the active role that complement plays in the development of PNH, current therapeutic options for the pathology involve the use of molecules capable of inhibiting this immune system. In Italy the drugs currently approved and available are eculizumab and ravulizumabmonoclonal antibodies that inhibit the terminal portion of the complement cascade (protein C5), and pegcetacoplan, which acts further upstream, inhibiting the expression of the C3 protein. “Furthermore, here at the Molinette Hospital, thanks to the activation of a compassionate use protocol, we have the possibility of also administering iptacopana powerful experimental inhibitor of complement factor B,” says Dr. Beggiato.
Inhibitors of the complement system have changed the natural history of PNHreducing thrombotic events by 92% and bringing the 97% patient survival rate, a value comparable to that of the general population. “The most used drug is certainly ravulizumab, which thanks to its longer half-life requires intravenous administration every eight weeks,” explains the hematologist. “Lengthening the period between infusions, compared to the two weeks between eculizumab administrations, also allowed an improvement in terms of patients’ quality of life”.
THE IMPORTANCE OF CAREFUL PATIENT MONITORING
In the EPN, Despite the effectiveness of therapy with complement inhibitors, there may sometimes be residual hemolytic crises during treatment: the so-called “breakthrough hemolysis”.”. This type of relapse can be attributable to two main factors: inadequate plasma level of the drug, due to insufficient dosage (pharmacokinetic breakthrough hemolysis), or concomitant presence of conditions that activate complement (pharmacodynamic breakthrough hemolysis), including infections, trauma, surgeries and pregnancy. “These episodes are treated with extra doses of eculizumab and, when possible, with therapy aimed at resolving the underlying cause,” explains Dr. Beggiato. “As regards episodes of pharmacokinetic breakthrough hemolysis, however, it is sufficient to bring forward the administration of the drug, for example by treating patients with eculizumab infusions every ten days instead of waiting the usual two weeks”.
Typically, patients with PNH respond well to complement inhibitor therapy, but there are exceptions. “For these “refractory” cases we have the possibility of measuring the levels of CD55 and CD59 to evaluate the clinical picture. It is not a standard test, but a flow cytometric test that we ‘borrow’ from the atypical hemolytic uremic syndrome”, explains the hematologist. “Otherwise, under normal conditions, monitoring of patients is carried out through monthly examinationswhich prevent blood counts, renal function, transaminases and hemolysis indices, and semester examsin which the size of the PNH clone is evaluated [la conta del numero di cellule colpite dalla malattia, N.d.R.]. In the end, for patients who have had a significant onset of the disease, or who are subject to thrombotic events, additional checks are carried outsuch as CT (Computerized Axial Tomography) of the chest and abdomen”.
CARE OF PATIENTS WITH PNH IN PIEDMONT AND VALLEY OF AOSTA
“In Piedmont, almost all hematology departments are able to take care of patients suffering from paroxysmal nocturnal hemoglobinuria”, explains Dr. Beggiato. “Only the smaller centers, which do not have the possibility of carrying out therapy with complement inhibitors, proceed with sending the patient to the structures with greater expertise. The presence of a national pathology registry – in which all professionals in the sector participate with data entry – helps in the management of patients, given that, Unfortunately, neither PDTA (Diagnostic-Therapeutic Care Paths) nor GIC (Interdisciplinary Treatment Groups) still exist. specific for paroxysmal nocturnal hemoglobinuria. For the moment, we discuss the most complex cases of PNH in a collegial manner, but on an informal level, often taking advantage of the opportunities offered by the Piedmont-Valle d’Aosta Interregional Oncology Network. We hope that in the future there will be the possibility of formalizing this type of meeting also for the EPN, perhaps with the help of regional institutions and with the collaboration of the Interregional Coordination Center for Rare Diseases of Piedmont and Valle d’Aostawhich is located at the S. Giovanni Bosco Hospital in Turin”.