Abstract

BACKGROUND

Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults with poor prognosis. Effective treatment is urgently needed. Recent studies demonstrated neurogliomal synaptic communication through AMPA and NMDA receptors promotes glioma invasion and progression in vitro and in vivo. Therefore, dual blocking AMPA and NMDA receptor therapy is a potential enhancing strategy to prevent and to treat GBM progression given the two blockers act through different anti-glioma mechanisms.

OBJECTIVE/HYPOTHESIS

We hypothesize that adding AMPA blocker Perampanel (An anti-seizure medication) and NMDA blocker Memantine (An anti-dementia medication) to standard temozolomide plus radiation therapy (Stupp’s regimen) for the treatment of newly diagnosed GBM may prevent tumor progression. It may also reduce the frequency of onset/recurrence of seizure episodes and possibly improve radiation related cognition impairment.

STUDY DESIGN

This is a randomized, active controlled, open label, two arm phase II study of efficacy of treatment of GBM with combination therapy (dual AMPA and NMDA receptor blockers plus standard therapy) versus standard therapy. In the combination therapy arm, patients take Perampanel 2 mg daily and Memantine 5 mg bid, starting from -14 days to +14 days from initiation of concurrent chemo-radiation therapy. Titrating up at a 2 mg increment for Perampanel and 5 mg bid increment for Memantine until reaching MTD. If the patient has AE >= grade 2, then reduce doses at a decrement of 2 mg for Perampanel and decrement of 5 mg bid for Memantine. In the standard therapy arm, the patients are treated with Stupp’s regimen.

PRIMARY AND SECONDARY ENDPOINTS

PFS, 12, 24 month survival rates and response duration. Safety will be assessed by CTCAE V5. We will use Kaplan-Meier estimates for survival data and a stratified log-rank test for the randomization strata.

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults with poor prognosis. Effective treatment is urgently needed. Recent studies demonstrated neurogliomal synaptic communication through AMPA and NMDA receptors promotes glioma invasion and progression in vitro and in vivo. Therefore, dual blocking AMPA and NMDA receptor therapy is a potential enhancing strategy to prevent and to treat GBM progression given the two blockers act through different anti-glioma mechanisms. OBJECTIVE/HYPOTHESIS We hypothesize that adding AMPA blocker Perampanel (An anti-seizure medication) and NMDA blocker Memantine (An anti-dementia medication) to standard temozolomide plus radiation therapy (Stupp’s regimen) for the treatment of newly diagnosed GBM may prevent tumor progression. It may also reduce the frequency of onset/recurrence of seizure episodes and possibly improve radiation related cognition impairment. STUDY DESIGN This is a randomized, active controlled, open label, two arm phase II study of efficacy of treatment of GBM with combination therapy (dual AMPA and NMDA receptor blockers plus standard therapy) versus standard therapy. In the combination therapy arm, patients take Perampanel 2 mg daily and Memantine 5 mg bid, starting from -14 days to +14 days from initiation of concurrent chemo-radiation therapy. Titrating up at a 2 mg increment for Perampanel and 5 mg bid increment for Memantine until reaching MTD. If the patient has AE >= grade 2, then reduce doses at a decrement of 2 mg for Perampanel and decrement of 5 mg bid for Memantine. In the standard therapy arm, the patients are treated with Stupp’s regimen. PRIMARY AND SECONDARY ENDPOINTS PFS, 12, 24 month survival rates and response duration. Safety will be assessed by CTCAE V5. We will use Kaplan-Meier estimates for survival data and a stratified log-rank test for the randomization strata.

Acute cerebellar syndrome can be caused by high doses of cytarabine, but it has not been described in patients with acute lymphoblastic leukemia (ALL) who received hyper-CVAD chemotherapy. Herein, we report two cases with histories of positive Philadelphia chromosome B-cell ALL who developed acute cerebellar syndrome after the exposure to relatively low doses of cytarabine in the second cycle of hyper-CVAD regimen. The cerebellar symptoms were attenuated by cytarabine discontinuation and administration of steroids. This case report provides detailed discussions on the treatments, the potential role of methotrexate in cytarabine-induced cerebellar syndrome, and the importance of carefully monitoring renal function during hyper-CVAD treatment.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive disease that originates from lymphocytes and develops in the central nervous system. There is no standard consolidation/maintenance therapy for PCNSL. While there exists a variety of options, the high chance of inferior outcomes for elderly patients and the risk of neurotoxicity requires exploration of alternative options for consolidation/maintenance therapy for PCNSL in the elderly population with CNS lymphoma. We treated one 77-year-old patient with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor that crosses the blood-brain-barrier, as consolidation/maintenance therapy after induction therapy with high-dose methotrexate (HD-MTX) and rituximab plus temozolomide. This treatment resulted in good tolerance, further resolution of a small residue lymphoma, and sustained remission. The patient has completed one year of consolidation/maintenance therapy and is currently under clinical and imaging surveillance. She has survived 27 months without recurrence since diagnosis. This case shows the potential effectiveness of single agent ibrutinib as consolidation/maintenance therapy for PCNSL after induction therapy. More cases are needed to confirm the findings.

Abstract INTRODUCTION Primary CNS Lymphoma (PCNSL) is a rare and aggressive cancer that originates from lymphocytes and develops in the central nervous system. Standard induction therapy involves high-dose methotrexate (HD-MTX)-based chemotherapy, which achieves complete or partial response in most PCNSL patients. However, there is no standard consolidation therapy. We report one case in which ibrutinib, a Bruton’s tyrosine kinase inhibitor, replaced low-dose WBRT as consolidation therapy after induction by HD-MTX and rituximab. Ibrutinib treatment yielded good tolerance and further resolution of small residue lymphoma. CASE REPORT The patient is a 77-year-old female who presented with slurred speech, right-sided weakness, and difficulty word-finding in early 2020. Brain MRI found multifocal lesions, and biopsy of the largest lesion near the left lateral ventricle revealed diffuse large B cell lymphoma. The patient began HD-MTX at 6 g/m2 for the first cycle of induction therapy. She continued HD-MTX every two weeks, but dosage was reduced every cycle due to worsening renal function. Ultimately, MTX was discontinued after 6 cycles. Brain MRI showed significant response after HD-MTX except for small residue lymphoma at the biopsy area. 2nd line regimen rituximab and temozolomide was given to complete induction. Brain MRI was stable, but the small enhancing residue lymphoma at left peri-ventricle area was persistent after the induction therapy (uCR). Ibrutinib as consolidation therapy began after discussion with the patient. The patient tolerated 560 mg ibrutinib for 6 cycles initially, then switched to a reduced dose of 420 mg for cycles 7 and 8 due to neutropenia. Brain MRIs have been stable with resolution of the small lymphoma residue after 6 cycles of ibrutinib. The patient continues ibrutinib for the goal of one year of consolidation therapy. DISCUSSION Our case highlights the potential of single-agent ibrutinib as consolidation therapy for PCNSL after HD-MTX and rituximab/temzolomide induction therapy.

Abstract

INTRODUCTION

Primary CNS Lymphoma (PCNSL) is a rare and aggressive cancer that originates from lymphocytes and develops in the central nervous system. Standard induction therapy involves high-dose methotrexate (HD-MTX)-based chemotherapy, which achieves complete or partial response in most PCNSL patients. However, there is no standard consolidation therapy. We report one case in which ibrutinib, a Bruton’s tyrosine kinase inhibitor, replaced low-dose WBRT as consolidation therapy after induction by HD-MTX and rituximab. Ibrutinib treatment yielded good tolerance and further resolution of small residue lymphoma.

CASE REPORT

The patient is a 77-year-old female who presented with slurred speech, right-sided weakness, and difficulty word-finding in early 2020. Brain MRI found multifocal lesions, and biopsy of the largest lesion near the left lateral ventricle revealed diffuse large B cell lymphoma. The patient began HD-MTX at 6 g/m2 for the first cycle of induction therapy. She continued HD-MTX every two weeks, but dosage was reduced every cycle due to worsening renal function. Ultimately, MTX was discontinued after 6 cycles. Brain MRI showed significant response after HD-MTX except for small residue lymphoma at the biopsy area. 2nd line regimen rituximab and temozolomide was given to complete induction. Brain MRI was stable, but the small enhancing residue lymphoma at left peri-ventricle area was persistent after the induction therapy (uCR). Ibrutinib as consolidation therapy began after discussion with the patient. The patient tolerated 560 mg ibrutinib for 6 cycles initially, then switched to a reduced dose of 420 mg for cycles 7 and 8 due to neutropenia. Brain MRIs have been stable with resolution of the small lymphoma residue after 6 cycles of ibrutinib. The patient continues ibrutinib for the goal of one year of consolidation therapy.

DISCUSSION

Our case highlights the potential of single-agent ibrutinib as consolidation therapy for PCNSL after HD-MTX and rituximab/temzolomide induction therapy.

Abstract

INTRODUCTION

Primary CNS lymphoma is a rare aggressive hematological malignancy. Current chemotherapy for induction phase is HD-MTX single agent or HD-MTX based combination regimen. We report a rare case whose left and right parietal lymphoma lesions in the brain responded to different induction therapy regimens during the induction phase.

CASE REPORT

A 43-year-old female presented with seizure and her brain MRI showed bilateral parietal brain lesions in January of 2020. Biopsy and work-up revealed primary CNS diffuse large B-cell lymphoma (DLBCL). The patient underwent HD-MTX therapy. Brain MRI showed clear progression of left parietal lymphoma but stable right parietal lymphoma after two cycles of HD-MTX at 8 g/m2. The treatment was switched to a rituximab 750 mg/m2 weekly and temozolomide 150 mg/m2 daily one-week-on and one-week-off regimen. After 8 weeks, her brain MRI showed nearly complete response of her left parietal lymphoma to rituximab/temozolomide but progression of her right parietal lymphoma. She was switched back to HD-MTX and completed total 8 cycles. Her right parietal lymphoma lesion showed complete response to HD-MTX. The patient is doing well and has been off the treatment over the past 10 months and is waiting for consolidation therapy with autologous stem cell transplantation that has been postponed due to the COVID pandemic.

DISCUSSION

Our case highlights the very rare heterogenous feature of primary CNS lymphoma responding to different treatment regimen. Biopsy of bilateral heterogeneous lesions may be indicated to compare the different molecular features of the lymphoma to find underlying mechanism if they respond to treatment differently. Specific treatment regimen should be selected based on the responsiveness of CNS lymphoma lesions or combination therapy is selected to cover the heterogeneous susceptibility to chemotherapy regimens.

Abstract INTRODUCTION Primary CNS lymphoma is a rare aggressive hematological malignancy. Current chemotherapy for induction phase is HD-MTX single agent or HD-MTX based combination regimen. We report a rare case whose left and right parietal lymphoma lesions in the brain responded to different induction therapy regimens during the induction phase. CASE REPORT A 43-year-old female presented with seizure and her brain MRI showed bilateral parietal brain lesions in January of 2020. Biopsy and work-up revealed primary CNS diffuse large B-cell lymphoma (DLBCL). The patient underwent HD-MTX therapy. Brain MRI showed clear progression of left parietal lymphoma but stable right parietal lymphoma after two cycles of HD-MTX at 8 g/m2. The treatment was switched to a rituximab 750 mg/m2 weekly and temozolomide 150 mg/m2 daily one-week-on and one-week-off regimen. After 8 weeks, her brain MRI showed nearly complete response of her left parietal lymphoma to rituximab/temozolomide but progression of her right parietal lymphoma. She was switched back to HD-MTX and completed total 8 cycles. Her right parietal lymphoma lesion showed complete response to HD-MTX. The patient is doing well and has been off the treatment over the past 10 months and is waiting for consolidation therapy with autologous stem cell transplantation that has been postponed due to the COVID pandemic. DISCUSSION Our case highlights the very rare heterogenous feature of primary CNS lymphoma responding to different treatment regimen. Biopsy of bilateral heterogeneous lesions may be indicated to compare the different molecular features of the lymphoma to find underlying mechanism if they respond to treatment differently. Specific treatment regimen should be selected based on the responsiveness of CNS lymphoma lesions or combination therapy is selected to cover the heterogeneous susceptibility to chemotherapy regimens.