Expanding the Indications for Ibrutinib: Complete Remission Obtained By Induction with Ibrutinib Followed By Consolidative Ahsct in Refractory Primary CNS Lymphoma
Bibliographic record
Abstract
Introduction Primary central nervous system lymphoma (PCNSL) is an exceedingly rare and aggressive sub-type of Non-Hodgkin's Lymphoma. Despite initial polychemotherapy that includes High-Dose Methotrexate (HD-MTX), over half of patients will develop recurrent or refractory disease that requires salvage therapy.1 Ibrutinib, a Bruton's tyrosine kinase inhibitor, has become an alternative for salvage treatment in relapsed or refractory PCNSL (RR-PCNSL) that is particularly useful in patients who are ineligible for re-induction with HD-chemo. In RR-PCNSL, Ibrutinib led to a progression free survival (PFS) of roughly 5 months when used as monotherapy2,3 and 15 months when used as add-on therapy.4 While its role as salvage treatment has been documented, its use to facilitate consolidative autologous hematopoietic stem cell transplant (AHSCT) in RR-PCNSL is not currently known. The following case describes the first known report of a patient with RR-PCNSL who achieved persistent complete remission following Ibrutinib salvage treatment and consolidative AHSCT. Case Description A 64-year-old male presented to the emergency department with a two-week history ptosis, visual abnormalities, confusion, and increasing fatigue. On physical exam, he was found to have bilateral mydriasis, left third nerve cranial palsy, severe left-sided ptosis, and restricted upwards and downward gaze of the right eye. A contrast-CT was performed which showed multiple areas of abnormal enhancement throughout the frontal lobes, corpus callosum, and midbrain associated with significant vasogenic edema. These findings were confirmed on MRI. He underwent a stereotactic guided burr hole biopsy which was consistent with diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry performed on the tissue showed that the neoplastic cells were CD3(-), CD5(-), CD20(+), CD10(-), BCL2(subset +), BCL6(+), MUM1(+) and Cyclin D1(-). Staging CT and bone marrow biopsy showed no evidence of systemic disease. He was diagnosed with PCNSL and went on to receive induction therapy with Rituximab, Methotrexate, Procarbazine, and Vincristine (R-MPV) with curative intent and received a total of 7 cycles. Initially, he had a significant radiographic response with a repeat MRI post cycle 4 showing only a few small areas of residual enhancement. However, after completion of the 7 cycles of R-MPV, his MRI showed evidence of disease progression with both new and enlarging intra-axial lesions. Given his ECOG of 0 and lack of comorbidities, it was decided that he would proceed with salvage treatment with Cytarabine and Etoposide with curative intent for refractory PCNSL. Unfortunately, after only four weeks of receiving cycle one of Cytarabine and Etoposide, a repeat MRI showed evidence of disease progression. He was then transitioned to palliative therapy with prednisone up until December 2017, at which point he was able to obtain Ibrutinib on a compassionate basis. He was started on Ibrutinib salvage therapy and achieved radiographic evidence of complete remission after four months of treatment. There were minimal adverse effects of Ibrutinib therapy, most notably a severe neutropenia requiring a temporary discontinuation of therapy for two weeks. He underwent consolidative AHSCT with Thiotepa, Busulfan and Melphalan conditioning in August 2018. His post-transplant course was complicated by culture negative febrile neutropenia with a subsequent source determined to be Clostridium difficile for which he was treated. An MRI head performed 3 months after his AHSCT showed no evidence of recurrent or residual disease. He continues to be followed by the Hematology Service in Newfoundland and has remained in complete remission since. Conclusions This case demonstrates the feasibility of a salvage approach using Ibrutinib followed by AHSCT when standard salvage options have been exhausted in refractory PCNSL. OffLabel Disclosure: Ibrutinib's indications do not currently include use as a induction treatment prior to AHSCT in refractory/recurrent PCNSL.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".