A Phase II study assessing Long-Term Response to Ibrutinib Monotherapy in recurrent or refractory CNS Lymphoma

Authors

Christian Grommes

Subhiksha Nandakumar

Lauren R. Schaff

Igor Gavrilovic

Thomas J. Kaley

Craig P. Nolan

Nikolaus Schultz

Lisa M. DeAngelis

Ingo K. Mellinghoff

Doi

10.1158/1078-0432.CCR-24-0605

PMID: 38995739 · DOI: 10.1158/1078-0432.CCR-24-0605 · Journal: Clinical Cancer Research (2024)

TL;DR

This single-center phase I/II trial (NCT02315326) at MSK treated 46 patients with relapsed/refractory primary (PCNSL, n=31) or secondary (SCNSL, n=15) CNS lymphoma with single-agent ibrutinib (mostly 840 mg/day). Response rates were 74% in PCNSL (12 CRs) and 60% in SCNSL (7 CRs), with ~10% of patients achieving durable (>3 year) responses. Exploratory genomic analysis using the MSK-HemePACT panel on archival tumor and paired CSF identified TBL1XR1 mutations as associated with significantly longer PFS on ibrutinib (16.5 vs 3.1 months, p=0.0075), and CSF ctDNA clearance within 4 weeks correlated with complete and long-term response PMID:38995739.

Cohort & data

  • 46 patients with r/r CNS lymphoma: 31 PCNSL + 15 SCNSL; median age 68 (range 21–90); median 2 prior therapies; all previously received methotrexate PMID:38995739.
  • Single-center investigator-initiated trial at Memorial Sloan Kettering (NCT02315326); 3 patients dosed at 560 mg, 43 at 840 mg daily.
  • Median follow-up 49.9 months (PCNSL) and 62.1 months (SCNSL).
  • Archival tumor biopsies available in 25/31 PCNSL cases; paired pre-/on-treatment CSF (CSF1/CSF2) available for 14 patients.
  • Sequencing: MSK-HemePACT targeted panel (585 cancer genes, hematologic-focused) on tumor and CSF ctDNA; matched germline.
  • Data deposited in cBioPortal as study pcnsl_msk_2024.

Key findings

  • PCNSL response: 23/31 (74%) responded, including 12 CR and 11 PR. Median PFS 4.5 months (95%CI 2.8–9.2); 1y-PFS 23.7%, 2y 13.5%, 3y 10.1%. Median OS 25.4 months. Median DOR 5.5 months PMID:38995739.
  • SCNSL response: 9/15 (60%) responded, including 7 CR. Median PFS 5.3 months (95%CI 1.3–14.5); 1y-PFS 31.1%, 3y-PFS 20.7%. Median DOR 8.7 months.
  • Long-term responders: 5/46 (~11%) had ongoing responses >3 years on single-agent ibrutinib.
  • TBL1XR1 and response: PCNSLs with TBL1XR1 mutations (9 patients) had PFS 16.5 months (95%CI 2.5–40.0) vs 3.1 months (95%CI 2.5–4.5) in wild-type (log-rank p=0.0075, HR 0.29, 95%CI 0.11–0.76). All TBL1XR1 mutations mapped to WD40 domains, likely loss-of-function.
  • TBL1XR1 not prognostic under SOC: In an independent cohort of 177 MSK PCNSLs treated with standard of care, TBL1XR1 status was not associated with outcome, suggesting predictive rather than prognostic value for ibrutinib.
  • MYD88 mutations: Associated with longer PFS on ibrutinib (9.2 vs 2.9 months; p=0.027, HR 0.39).
  • CARD11 mutations: 6 patients; associated with shorter PFS (2.2 vs 5.5 months), consistent with prior reports of CARD11-mediated ibrutinib resistance in B-cell malignancies.
  • BCR pathway landscape in PCNSL cohort: MYD88 72%, CD79B 48%, CARD11 24%, TBL1XR1 36%; 21/25 (84%) non-germinal center (Hans classifier).
  • CSF ctDNA kinetics: Paired CSF1/CSF2 in 14 patients. Complete ctDNA clearance within 4 weeks in 8/14 (57%); 3/14 reduced; 3/14 unchanged. Patients achieving CR on imaging had undetectable ctDNA at week 4, while 67% of non-CR patients had persistent ctDNA. Patients with PFS ≥6 months had a median 100% reduction in ctDNA alterations vs 30.8% for PFS <6 months (p=0.018).
  • Pharmacokinetics: Peak plasma ibrutinib ~191.7 ng/mL at 2h; CSF concentration 1.386 ng/mL (3 nM) at 560 mg and 2.695 ng/mL (6 nM) at 840 mg. Plasma level correlated with CSF level.
  • Safety: No grade 5 events; no treatment-related deaths. Most common AEs: thrombocytopenia (83%), hyperglycemia (57%), hypercholesterolemia (48%), ALT elevation (48%). One case of aspergillosis in a heavily corticosteroid-pretreated patient.

Genes & alterations

  • TBL1XR1 — WD40-domain mutations (likely LoF); present in 36% of PCNSLs; predictive of prolonged ibrutinib response (PFS 16.5 vs 3.1 months, p=0.0075) PMID:38995739.
  • MYD88 — mutated in 72% of PCNSL cohort; associated with longer PFS on ibrutinib (9.2 vs 2.9 months, p=0.027).
  • CD79B — mutated in 48% of PCNSL cohort; canonical BCR-pathway driver in PCNSL.
  • CARD11 — mutated in 24% of PCNSL; coiled-coil-domain mutations associated with poor response and shorter PFS (2.2 vs 5.5 months), consistent with known ibrutinib-resistance mechanism in DLBCL.

Clinical implications

  • Single-agent ibrutinib 840 mg daily is active and tolerable in heavily pretreated r/r PCNSL and secondary CNS lymphoma, supporting its inclusion in NCCN r/r PCNSL guidelines PMID:38995739.
  • TBL1XR1 mutation status is a candidate predictive biomarker for durable benefit from BTK inhibition in PCNSL; warrants prospective validation with second-generation BTK inhibitors.
  • CARD11 coiled-coil mutations mark likely primary ibrutinib resistance.
  • Paired pre- and on-treatment CSF liquid biopsy using the MSK-HemePACT panel enables early assessment of response; clearance of CSF ctDNA within 4 weeks is a candidate surrogate for complete and durable response.
  • Consider fungal surveillance (BD-glucan, galactomannan) in patients on chronic corticosteroids receiving ibrutinib.

Limitations & open questions

  • Single-center, non-randomized trial; modest sample size (n=46) limits the statistical weight of biomarker associations — authors explicitly frame TBL1XR1/MYD88/CARD11 findings as exploratory.
  • Archival tumor tissue was unavailable in 6/31 PCNSL and many patients lacked rebiopsy at recurrence, so resistance mechanisms at progression are under-sampled.
  • Only 14 patients had paired CSF1/CSF2 samples for ctDNA kinetic analysis.
  • SCNSL cohort is heterogeneous (n=15) and underpowered for genomic subgroup analysis.
  • Dose comparison between 560 mg and 840 mg is confounded by small 560 mg subset (n=3).
  • Whether TBL1XR1-driven benefit generalizes to second-generation BTK inhibitors (e.g., tirabrutinib) is an open question the authors flag for ongoing trials.

Citations from this paper used in the wiki

  • “Tumor responses were observed in 23/31 (74%) PCNSLs and 9/15 (60%) SCNSLs, including 12 complete responses in PCNSL and 7 in SCNSL.” (Abstract)
  • “PCNSL patients with alterations in TBL1XR1 had a significantly longer progression-free survival of 16.5 months (95%CI: 2.5–40.0) compared to 3.1 months (95%CI: 2.5–4.5)… (Log-rank p=0.0075, HR: 0.29, 95%CI: 0.11–0.76).” (Results)
  • “All TBL1XR1 mutations mapped to its WD40 domains… and most likely represent loss of function events.” (Results)
  • “In patients with a complete response, ctDNA could no longer be detected after 4 weeks of ibrutinib therapy.” (Results)
  • “The data generated in this study are publicly available in cBioPortal for Cancer Genomics at https://www.cbioportal.org/study/summary?id=pcnsl_msk_2024” (Data Availability)

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