New guideline on diagnosing and treating mantle cell lymphoma

Blood cancers

By Priya Venkatesan

15 Nov 2023

New comprehensive mantle cell lymphoma guidelines published by the British Society for Haematology will be useful to physicians across the globe, an international expert says.

According to Dr Carlo Visco, an Associate Professor of Haematology at the University of Verona, the recently published guidelines describe current treatment strategies available in most countries and “offer insights to clinicians for several intriguing difficult-to-treat scenarios”.

The comprehensive guidelines [link here] begin with a pre-treatment evaluation, including histopathological, clinical and frailty assessments along with genetic testing for TP53 aberrations – the “strongest predictors of poor responses to chemoimmunotherapy, early disease progression and mortality”.

Initial clinical assessment should include evaluation of B symptoms, hepatosplenomegaly and lymphadenopathy; neurological and gastrointestinal symptoms; ECOG performance status, fitness for immunochemotherapy, and frailty; and blood tests including a full blood count, biochemistry including urate and lactate dehydrogenase, and HIV and hepatitis B and C virology.

Echocardiography should be considered, and patients should be offered fertility counselling or preservation if appropriate, the authors suggest. Frailty should preferably be assessed with formal tools such as the Geriatric 8 screening tool or the Cumulative Illness Rating Scale for Geriatrics and the Geriatric Assessment in Haematology.

According to the guidance, staging of MCL should be undertaken with the tools 18F-FDG PET/CT or CT, performing a bone marrow biopsy and aspirate if required. Pre-treatment baseline risk should be assessed using the independently validated MCL international prognostic index (MIPI) or combined MIPI (MIPI-C). Localised radiotherapy (4–24 Gy) or active observation should be considered for patients with early-stage disease. More extensive staging should also be considered for localised radiotherapy candidates.

Intensive chemotherapy and ASCT for fit younger patients

For patients who require treatment and are deemed fit (and typically younger than 65 years), intensive chemotherapy induction and autologous stem cell transplantation (ASCT) consolidation remain the current standard of care, the guideline authors noted.

The first-line induction regimen should contain rituximab and high-dose cytarabine. Patients obtaining an objective response to induction therapy should be offered consolidation ASCT and maintenance rituximab after ASCT. Alternative consolidation strategies should be considered for patients with a TP53 mutation.

First-line rituximab regimens for patients unsuitable for ASCT

Rituximab-based regimens should be offered as a standard of care to untreated patients deemed unsuitable for cytarabine-based induction and ASCT, the guidelines advise.

R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), rituximab–bendamustine, R-BAC (rituximab–bendamustine plus cytarabine), and VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) are options for such patients. Rituximab maintenance should be considered following R-CHOP or R-bendamustine induction but not after R-BAC outside of a clinical trial.

For initial treatment of appropriate frail patients, rituximab-based treatment – R- chlorambucil, R-CVP (rituximab, cyclophosphamide, vincristine, and prednisolone), attenuated R-bendamustine, or attenuated R-CHOP can be considered, along with a review by a geriatrician.

For indolent asymptomatic MCL, active observation is recommended. Dr Visco noted in his editorial: “We have moved from an era where all patients were treated right after diagnosis, to the recognition of indolent forms that do not need immediate treatment upfront.”

Ibrutinib monotherapy at first relapse

A covalent Bruton tyrosine kinase inhibitor (cBTKi) should be offered for patients relapsing after first-line immunotherapy, the guidelines recommend. The UK authors suggest cBTKi ibrutinib monotherapy should be offered as the standard of care option; if ibrutinib, acalabrutinib, or zanubrutinib are all available, treatment should be individualised based on specific toxicity profiles.

The CAR T-cell therapy brexucabtagene autoleucel (Tecartus), which is conditionally authorised in Europe, should be offered for relapsed or refractory MCL after at least two lines of previous therapy, including anti-CD20 antibody-containing immunochemotherapy and a BTKi.

“This therapy, representing the first generation of CAR-T in MCL, has radically changed the therapeutic paradigm of these patients,” wrote Dr Visco in an editorial accompanying the guidelines. Potential candidates for future CAR-T treatment should be risk assessed at first relapse before initiation of a BTKi, the authors noted.

They note there is no standard therapeutic approach for patients who relapse on cBTKi and are unsuitable for CAR-T (or who have not responded to CAR-T), and as such this remains an unmet need. Clinical trials should be considered for such patients, along with immunotherapy (R-BAC preferred) or a non-covalent BTKi such as pirtobrutinib.

Other recommendations include allogeneic stem cell transplantation (alloSCT) to be considered for fit patients after failure with immunochemotherapy, cBTKi, and CAR-T, although data for alloSCT are limited, and benefits may be negated by graft-versus-host disease.

Also, central nervous system relapse of MCL is uncommon and incompletely studied; the guideline recommends ibrutinib in previously untreated patients, but does not recommend primary CNS prophylaxis with CNS penetrating agents.

“Overall, we need to congratulate with UK colleagues for putting together these guidelines, that will serve for the community of MCL dedicated physicians all over the world. It seems we are on the right track for letting the mantle out of the bag,” Dr Visco concluded.

Read the guidelines in full here

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