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Ibrutinib compared to immuno-chemotherapy for central nervous system relapse of mantle cell lymphoma


Central nervous system ( CNS ) relapse of mantle cell lymphoma ( MCL ) is a rare phenomenon for which a standard of care has not been identified.
Responses to conventional treatment for CNS-MCL are poor, with median survival of less than 6 months.
Ibrutinib ( Imbruvica ) is approved for relapsed / refractory mantle cell lymphoma, and small series demonstrated efficacy in CNS disease due to its ability of crossing the blood-brain barrier ( BBB ).

The aim of the study was to report the outcome of MCL patients with documented CNS involvement at relapse, and analyze response and survival of patients treated with Ibrutinib compared to standard therapy.

Researchers have retrospectively analyzed a multi-center series of consecutive patients with CNS relapse of systemic mantle cell lymphoma treated between 2000 and 2019 in 38 centers ( 20 internationals and 18 from FIL [ Fondazione Italiana Linfomi ] ).
The cohort included 39 patients receiving standard therapy as described in previous reports.
Overall survival ( OS ) was estimated from the time of initiation of CNS-MCL directed therapy until death.

Eighty-four patients were analyzed: 58 patients ( 69% ) were treated with standard immuno-chemotherapy ( CHT ) ( standard cohort, SC ), while 26 patients ( 31% ) were treated with Ibrutinib ( Ibrutinib cohort, IC ).
The two cohorts displayed similar characteristics: median age was 62 years ( range: 38-84 ) in standard cohort and 63 years ( range: 48-77 ) in Ibrutinib cohort ( p=0.26 ); blastoid variant was diagnosed in 29% standard cohort and 24% Ibrutinib cohort patients ( p=0.78 ); MIPI score was high in 63% standard cohort and in 71% Ibrutinib cohort patients ( p=0.64 ).
Median prior therapies for mantle cell lymphoma preceding CNS relapse was 1 ( range: 1-5 ) in the standard cohort and 1 ( range: 1-2 ) in the Ibrutinib cohort ( p=0.15 ).
Median time from initial MCL diagnosis to CNS relapse was 15 months ( range: 2-122 ) in the standard cohort, and 19 months ( range: 1-86 ) in the Ibrutinib cohort ( p=0.45 ).

In the standard cohort, treatment for CNS relapse consisted of Rituximab plus BBB crossing therapies in 28 patients ( 48% ), Rituximab plus Bendamustine-based in 6 patients ( 11% ), intrathecal ( IT ) chemotherapy only in 17 patients ( 29% ) and radiotherapy in 7 patients ( 12% ).
BBB crossing therapies consisted mainly of HD-Methotrexate, alone in 7 patients ( 25% ), combined with HD-Ara-C in 19 patients ( 68% ), and 2 patients ( 7% ) received Ifosfamide-based.

In the standard cohort, intrathecal therapy was added in 45 patients ( 78% ). Patients in the Ibrutinib cohort received Ibrutinib 560 mg p.o. daily until progression or toxicity; intrathecal chemotherapy was given concurrently in 12 patients ( 46% ).

Data for response assessment were available for 79 patients ( 89% ). Overall-response rate ( ORR ) was 72% in the Ibrutinib cohort and 39% in the standard cohort, while complete response ( CR ) rate was 42% and 17%.
Considering patients receiving BBB crossing treatments within the standard cohort, ORR was 46% and CR rate 22%.
The difference between CR rate in the Ibrutinib cohort and BBB crossing therapies group was statistically significant ( 42% vs 22%, p=0.02 ).

With a median follow-up of 4.3 months, the 1-year overall survival of the entire study population was 27%.
Ibrutinib conferred a statistically significant superior 1-year OS compared to standard cohort ( 61% vs 16%; hazard ratio, HR=0.29, p less than 0.001 ).
Similarly, overall survival was confirmed superior with Ibrutinib compared to patients receiving BBB crossing therapies ( 1-year rates: 59% vs 25%; HR=0.39, p=0.011 ).

Intrathecal therapy was not of additional benefit in the Ibrutinib cohort ( intrathecal vs no-intrathecal: 1-year OS 63% vs 60%, p=0.72 ) or in the standard cohort ( 1-year OS 13% vs 25% p=0.45 ).

In the Ibrutinib cohort no unexpected toxicity was reported, including no cases of invasive fungal infection.

In conclusion, this is the first large cohort analyzing outcome of patients treated with Ibrutinib for CNS relapse of mantle cell lymphoma.
With the usual limitations of a retrospective analysis, Ibrutinib was associated with an improved response and survival compared to standard immuno-chemotherapy in this difficult to treat population, with half of patients alive at 1 year. ( Xagena )

Source: EHA25 - European Hematology Association Virtual Meeting, 2020

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