Novel targeted therapies should be included in immunochemotherapy regimens for mantle cell lymphoma (MCL) whenever possible, according to new European guidelines.
Co-produced by the European Haematology Association (EHA) and the European MCL Network, the latest advice stresses that regimens including covalent Bruton tyrosine kinase inhibitors (cBTKis), particularly ibrutinib, are now the standard of care for young, fit patients.
They also advise active observation for any asymptomatic disease and include recommendations for CAR T-cell therapy and other novel treatments in the second-line setting, while autologous stem cell transplantation (ASCT) is less broadly indicated.
“Immunochemotherapy has historically been the mainstay of treatment, but recent data indicate that addition of novel agents, especially cBTKi, may substantially improve outcome in younger and older patients, although a curative approach remains to be shown,” wrote the authors, including Dr Toby Eyre, consultant haematologist at Oxford University Hospitals NHS Foundation Trust.
“For patients with relapsed or refractory disease, treatment options are developing rapidly, including CAR-T cell therapy, novel BTK targeting agents, BCL2 inhibitors, and T-cell engagers,” they added.
Dr Toby Eyre
The new guidelines, published in HemaSphere [link here], recommend that MCL should be diagnosed by excision biopsy, preferably of a lymph node, with TP53 mutation status determined at the same time and a repeat biopsy performed whenever new treatment is required.
Disease should be routinely staged with CT scanning, bone marrow aspirate and biopsy, with PET-CT scan and gastrointestinal endoscopy advised for that suspected to be stage I–II.
“Practice over recent years has evolved from treating all patients at diagnosis to characterising those where active observation may be appropriate,” the guidelines note.
As such, they recommend that any asymptomatic patients are treated with active observation, with assessment every three months, while patients with limited stage disease may also be observed if they have low-risk disease features, but otherwise should be treated as per advanced stage disease.
For newly diagnosed advanced stage disease, first-line treatment should be determined by the patient’s age and fitness.
Patients younger than 65 years, or older than 65 years but fit, should be treated with cBTKI-containing immunochemotherapy regimens, such as rituximab-bendamustine-cytarabine (R-CHOP) plus ibrutinib induction, followed by two years of ibrutinib and three years of rituximab maintenance.
In this setting, the guidelines now only recommend that ASCT is discussed with “selected patients if high-risk features are present”.
cBTKIs with rituximab are also recommended as first-line treatment for frail, older patients with advanced disease, alongside rituximab-containing chemotherapy regimens and bendamustine-rituximab with acalabrutinib, generally followed by two years of maintenance rituximab.
Patients with high-risk disease – typically defined a high-risk MIPI score, high Ki67, blastoid or pleomorphic morphology, or a TP53 mutation or p53 overexpression – are also recommended cBTKi-containing induction, with or without autologous stem cell transplant (ASCT), followed by ibrutinib then rituximab maintenance.
Advice on progression
Upon each disease progression, the guidelines emphasise that treatment should be individualised by disease-risk features, patient-specific factors such as comorbidities, prior therapies, toxicities and patient preferences, and treatment-related factors.
Optimal treatment after relapse following time-limited cBTKi treatment “remains uncertain”, but retreatment with cBTKIs gives “reasonable outcomes”.
Relapsed patients who have not received a first-line cBTKi should be treated with a cBTKi-containing immunochemotherapy regimen, with the possible addition of venetoclax, although the drug is awaiting approval in this setting.
For patients who have failed first-line cBTKi-containing regimen, the guidelines recommend anti-CD19 CAR T-cell therapy or pirtobrutinib, although the former was recently rejected by NICE in this setting (see our story here).
The authors note that there are “few recent data supporting a role for ASCT in R/R MCL” and so recommend that the use of ASCT “should be discussed in patients failing CAR-T on a case-by-case basis, considering the patient’s comorbidities, high-risk disease features, and previous treatments”.
“ASCT may also be considered in select younger patients with high-risk features, in CR following CAR-T,” they advised.