Adnkronos Rome, May 16 (Adnkronos Salute) – Every year, in Lazio, there are an estimated 275 new cases of chronic lymphocytic leukemia (10% of the total diagnoses in Italy, equal to 2.750). It is a hematological neoplasm characterized by the accumulation of a particular type of white blood cells, called B lymphocytes, in the blood and lymphoid organs (bone marrow, lymph nodes, spleen) and by a variable course.
The median age at diagnosis is approximately 70 years, with patients often presenting with one or more comorbidities. Some may remain stable for more than 10 years, while others experience rapid deterioration. The clinical course of chronic lymphocytic leukemia can be complicated by multiple relapses. Hence the importance of effective and well-tolerated therapies, even in those who have to deal with a relapse of the disease. A decisive step forward is represented by an innovative targeted therapy, Pirtobrutinib, recently approved by the European Commission for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia, previously treated with a Btk inhibitor.
"Symptoms may include tiredness, rarely fever, night sweats and involuntary weight loss," says Luca Laurenti, associate professor of Hematology at the Fondazione Policlinico Universitario A. Gemelli Irccs in Rome, Università Cattolica del Sacro Cuore. "Swollen lymph nodes and a feeling of abdominal fullness due to an enlarged spleen may also be present, and sometimes lymphocytes are very high in the peripheral blood. The aim of treatment is to bring blood values and the size of the lymph nodes back to normal, achieving remission of the disease. The turning point in the treatment of chronic lymphocytic leukemia came with the arrival of inhibitors of the Btk protein, Bruton's tyrosine kinase, and inhibitors of the Bcl-2 protein, involved in the regulation of apoptosis, or programmed cell death. New treatments have allowed us to abandon traditional chemo-immunotherapy, which is burdened by heavy side effects, and today chronic lymphocytic leukemia can be treated with a combination of chemotherapy and immunotherapy. with targeted therapies that, in combination with other drugs, are able to ensure periods free from both disease progression and drug administration itself".
"The Policlinico Gemelli – explains Laurenti – is at the forefront in the treatment of this blood cancer, with at least 30 studies underway in phase 1, 2 and 3. For phase 1 it is the reference structure for Central and Southern Italy".
"The mechanism of action of targeted therapies is to directly interfere with the processes that regulate the proliferation and survival of leukemic cells," Laurenti continues. "When a relapse occurs, that is, when conditions reappear that, according to the guidelines drawn up by international scientific societies, require a second line of therapy, the patient is offered treatments that are not used in the first line. Pirtobrutinib, which is a non-covalent Btk inhibitor, fits right into this context and, based on the indication of the European regulatory agency, can be used starting from the second line in patients already treated with a covalent Btk inhibitor. In particular, the new molecule fills a therapeutic gap not only in the second but also in the third line of therapy, that is, in patients who have previously received both the covalent Btk inhibitor and the Bcl-2 inhibitor. These patients, until now, were deprived of effective therapies and had a poor survival rate."
The mechanism of action of "Pirtobrutinib is innovative - Laurenti remarks -. The new molecule is able to act even where previous generations of the same class of drugs have created resistance and lost therapeutic efficacy. Pirtobrutinib is able to overcome the resistance of covalent Btk inhibitors, thus effectively controlling the disease". The approval of the European Commission - a note reports - is supported by the data of the Bruin Cll-321 clinical study, the first randomized Phase 3 study in Cll conducted exclusively in patients previously treated with a Btk inhibitor. The study's primary endpoint, progression-free survival (PFS), was met at the predefined time point for the primary analysis (August 29, 2023) based on independent review committee (IRC) assessment, demonstrating that pirtobrutinib was superior to the investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR), both of which were included in the control arm.
At the updated analysis (August 29, 2024), pirtobrutinib reduced the risk of disease progression or death by 46% compared with IdelaR or Br (median PFS: 14,0 vs. 8,7 months), consistent with the primary analysis. PFS results were consistent across subgroups analyzed, including patients previously treated with venetoclax, and subgroups associated with poor prognosis, including those with TP53 mutation and/or 17p deletion, wild-type IGHV status, and complex karyotype. Additionally, the median time to subsequent treatment or death (Ttnt), a predefined and descriptive secondary endpoint in the study that may serve as an additional marker of disease control outcomes, was 24 months versus 11 months in the control arm (63% improvement; HR=0,37 [95% CI, 0,25-0,52]). The overall safety profile of patients treated with pirtobrutinib in the Bruin Cll-321 study was consistent with the safety data from the Phase 1/2 Bruin study, including adverse events of special interest. The most common adverse reactions of any grade were neutropenia, fatigue, diarrhea, anemia, rash, and bruising.
"This new indication offers an innovative treatment option for adults with relapsed or refractory chronic lymphocytic leukemia progressing on a covalent Btk inhibitor, addressing a key unmet need in this setting," said Elias Khalil, General Manager Lilly Italy Hub. "Lilly is committed to rapidly advancing the development of Pirtobrutinib and continuing to offer important new treatments to patients with hematologic malignancies."
Pirtobrutinib also previously received a conditional marketing authorization from the European Commission for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received a Btk inhibitor. Pirtobrutinib is approved in other countries and applications for additional indications have been submitted worldwide.