Lakshmi Nayak, MD, is the director of the Center for Central Nervous System Lymphoma and a senior physician at Dana-Farber Cancer Institute. She is also an associate professor of neurology at Harvard Medical School.

Dr Nayak on the Ongoing Investigation of Emavusertib Plus Ibrutinib in R/R PCNSL

“We are investigating the role [of emavusertib plus ibrutinib] in terms of efficacy. The population that is being studied [includes] patients who have progressed after BTK inhibition. We’re looking to target that mechanism of resistance to [BTK inhibition] in that regard, rather than target patients who never responded to BTK inhibition, which is a fraction of the patients.”

Lakshmi Nayak, MD, director, Center for Central Nervous System (CNS) Lymphoma, senior physician, Dana-Farber Cancer Institute; and associate professor, neurology, Harvard Medical School, discusses the mechanism of action of emavusertib (CA-4948) and how this mechanism provides the rationale for the drug’s ongoing investigation in combination with ibrutinib (Imbruvica) in patients with relapsed/refractory primary and secondary CNS lymphoma (PCNSL) in the part B expansion cohort of 

Emavusertib, an IRAK4 inhibitor, is being explored for its potential in treating patients with PCNSL, Nayak begins. One key advantage of this compound is its ability to cross the blood-brain barrier, a significant challenge in treating patients with brain tumors, she says. In preclinical studies, the agent demonstrated blood-brain barrier penetration, as well as activity against BTK-resistant cell lines, she notes. This is particularly relevant as resistance to BTK inhibitors, such as ibrutinib, poses a major hurdle in lymphoma management, particularly for patients with PCNSL, Nayak explains. The ability of this IRAK4 inhibitor to maintain activity in BTK-resistant models positions it as a potential next step in treatment after resistance to BTK inhibition develops, she reports. For patients who have initially responded to BTK inhibitors but later progressed, combinations containing this IRAK4 inhibitor could offer a strategy to target the resistance and restore efficacy, according to Nayak. In addition, there is potential for this agent to be explored in earlier lines of therapy, either alone or in combination with chemotherapy, to improve patient outcomes from the outset, she emphasizes.

Emavusertib has been studied in various oncologic indications, including both myeloid and lymphoid malignancies, Nayak notes. A safety study involving patients with PCNSL showed that the combination of the IRAK4 inhibitor with ibrutinib was well tolerated, she adds. Moving forward, part B of the TakeAim Lymphoma trial is investigating the efficacy of this regimen in patients with PCNSL who have progressed after previously achieving a response with a BTK inhibitor, with the hope of addressing resistance and improving outcomes in this challenging-to-treat patient population, Nayak concludes.

Videos

Lakshmi Nayak, MD, discusses the mechanism of action of emavusertib and the study of this drug relapsed/refractory primary and secondary CNS lymphoma.

Dr Nayak on the Investigation of Axi-Cel in CNS Lymphoma

Lakshmi Nayak, MD, director, Center for Central Nervous System (CNS) Lymphoma, senior physician, Dana-Farber Cancer Institute; associate professor, neurology, Harvard Medical School, discusses the investigation of axicabtagene ciloleucel (Yescarta; axi-cel) in a pilot study for patients with relapsed/refractory primary and secondary CNS lymphoma.

Notably, findings from this investigation were presented at the 

. The study concluded that axi-cel is both safe and effective in treating patients with these diseases, with no increased risk of immune effector cell-associated neurotoxicity syndrome (ICANS) compared with in systemic diffuse large B-cell lymphoma (DLBCL). At a median follow-up of 24 months, the median progression-free survival was 14.3 months (95% CI, 6.3-not reached [NR]), with an overall response rate of 94% and a complete response rate of 67%. Despite the high relapse rates typically associated with current CNS lymphoma treatments, axi-cel was effective and durable in this patient population. The median duration of response was 13.4 months (range, 1-30), and the median overall survival was 26.4 months (95% CI, 11.2-NR).

Cytokine release syndrome (CRS) occurred in 89% of patients, primarily at low grades, and ICANS occurred in 44% of patients, with 28% of patients experiencing grade 3 ICANS.

Axi-cel, which is a CD19-directed CAR T-cell therapy, has transformed the treatment of patients with relapsed/refractory systemic DLBCL, Nayak begins. 

 in the second- and third-line settings for the treatment of patients with large B-cell lymphoma, she says. Notably, this regulatory decision was based on findings from the phase 3 ZUMA-7 trial (NCT03391466). However, initial studies investigating this agent in systemic DLBCL excluded patients with CNS lymphoma, leaving the safety and efficacy of axi-cel in this patient subgroup unclear, Nayak emphasizes.

This pilot study was therefore conducted to primarily assess the safety of axi-cel in patients with CNS lymphoma, with additional end points comparing the incidence of adverse effects with this treatment in patients with CNS lymphoma to the incidence of those in other patient populations, she says. Additionally, as a secondary end point, the study evaluated the efficacy of axi-cel in this difficult-to-treat patient subgroup, Nayak concludes.

Lakshmi Nayak, MD, discusses the investigation of axi-cel in patients with relapsed/refractory primary and secondary CNS lymphoma.

Lakshmi Nayak, MD, senior physician, director, Center for Central Nervous System (CNS) Lymphoma, Center for Neuro-Oncology, Dana-Farber Cancer Institute, assistant professor, Neurology, Harvard Medical School, discusses the diagnosis of patients with primary CNS lymphoma (PCNSL).

PCNSL is a rare variant of extra-nodal non-Hodgkin lymphoma (NHL), Nayak begins. It accounts for about 4% of malignant CNS tumors, and its incidence has risen significantly in recent years, she reports. PCNSL is typically present in the brain and cerebrospinal fluid without evidence of systemic spread. The eyes and spinal cord can also be involved in this disease, although this is less frequent.

Most patients with PCNSL will first visit the emergency room or their general practitioner with worsening neurologic symptoms, Nayak says. Symptoms can include focal neurologic deficits, mental and behavioral changes, headaches, nausea, vomiting, papilledema, or seizures. These patients will then undergo baseline staging, which includes magnetic resonance imaging (MRI) of the brain, Nayak continues. The MRI scan will typically identify a single homogenously enhancing mass lesion in the supratentorial area with frontoparietal lobe involvement. Other tools recommended to assess the extent of disease are ophthalmologic evaluation, and CSF evaluation.

The majority of patients who develop PCNSL are 60 years of age or older, and the median age of diagnosis is around 65 years old, Nayak notes. Importantly, advanced age has been identified as an independent prognostic factor for worse patient outcomes for this disease. PCNSL can also develop in individuals who are immunocompetent or immunosuppressed due to HIV/AIDS, organ transplant, or immunosuppressive agents. Notably, the presence of a mass legion is more likely to be cancer rather than a different abnormality, she explains. However, histopathologic confirmation of the diagnosis through stereotactic biopsy is recommended to confirm diagnosis, Nayak concludes.

Lakshimi Nayak, MD, discusses the diagnosis of patients with primary CNS lymphoma.

Dr Nayak on the Identification of Primary CNS Lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive variant of extranodal non-Hodgkin lymphoma (NHL) that occurs in the brain, spinal cord, cerebrospinal fluid (CSF), or eyes in the absence of systemic disease. Although it responds favorably to chemotherapy and radiation, prognosis is inferior to that of other subtypes of NHL. PCNSL accounts for 3% of all brain tumors and 6% of all extranodal lymphomas, and approximately 90% of cases are classified as diffuse large B-cell lymphomas (DLBCLs), with T-cell lymphoma, low-grade lymphoma, and Burkitt lymphoma accounting for the remaining 10%.

Histopathology reveals malignant B cells in an angiocentric pattern with diffuse infiltration of the central nervous system (CNS), indistinguishable from systemic DLBCL, and gene-expression profiling demonstrates that the majority of PCNSLs are of the nongerminal center or activated B-cell–like (ABC) subtype.

 Age and performance status have been identified as independent predictors associated with prognosis.

 An early diagnosis by brain biopsy is preferable, followed by an evaluation of the extent of disease for staging and rapid institution of treatment; these are paramount to achieve neurologic recovery and improve survival.

Management of newly diagnosed PCNSL has evolved over the past several years and standard-of-care guidelines are based on data from both single-arm and randomized phase 2/3 trials. In general, high-dose methotrexate (HD-MTX) in combination with an alkylating agent, such as high-dose cytarabine and rituximab (Rituxan), is recommended for induction therapy, although the role of rituximab, particularly in elderly patients, is the focus of debate because of conflicting trial results.

 The majority of HD-MTX–based chemotherapy regimens have demonstrated complete response rates of 50% and overall response rates of up to 90%. Intrathecal chemotherapy is not utilized based on data from prior studies and only offered to patients with an insufficient CSF response to HD-MTX or to those who are unable to receive HD-MTX at a dose of at least 3 g/m

, which is required for adequate CSF penetration.

It is unclear whether patients with ocular involvement would benefit from the addition of local therapy in the form of intravitreal MTX or ocular radiation to systemic chemotherapy. Typically, local therapy is considered if systemic therapy fails to achieve ocular disease control or if there is ocular recurrence. Consolidation therapy is recommended after completion of induction in appropriate patients to improve long-term disease-free survival. Whole-brain radiation therapy (WBRT) has historically been used for consolidation; however, there is increasing evidence that WBRT results in delayed and irreversible neurocognitive impairment in patients who are 60 years or older, particularly when delivered in combination with HD-MTX.

 Given that the median age when receiving a diagnosis is 65 years, this approach is no longer preferred as first-line treatment and is reserved for salvage. Reduced-dose WBRT is under investigation in a randomized clinical trial.

Although there is a progression-free survival (PFS) benefit, the impact on long-term neurotoxicity remains to be seen.

 Over the past 10 years, long-term results of studies with high-dose chemotherapy followed by autologous stem cell transplant (HDC-ASCT) have demonstrated encouraging long-term PFS and overall survival (OS). Five-year PFS and OS rates of 81% to 83% have been reported specifically with thiotepa-based conditioning regimens, which are recommended over other conditioning regimens such as BEAM (carmustine, etoposide, cytarabine, and melphalan) or CBV (cyclophosphamide, carmustine, and etoposide), which have led to inferior outcomes.

Data from 2 European, multicenter, randomized studies (NCT01011920, NCT00863460) comparing WBRT and HDC-ASCT for consolidation have shown similar efficacy or slight improvement of outcomes on the ASCT arm.

 Importantly, both studies note improvement of neurocognitive function with ASCT and worsening with WBRT. However, many studies investigating the role of HDC-ASCT have included younger, healthier patients. Additionally, the treatment-associated mortality with ASCT has been variable, ranging from 0% to 14%. Although this approach remains attractive, it requires careful patient selection and treatment at a specialized center. Overall, fewer than 10% to 15% of patients are candidates for such therapy.

Nonmyeloablative chemotherapy regimens are also being considered for consolidation as an alternative to ASCT. Initial studies with high-dose etoposide and cytarabine (EA) have demonstrated encouraging results.

 Recent results from a randomized phase 2 study (NCT01511562), which compared EA with HDC-ASCT after induction plus MTR-A (HD-MTX, temozolomide [Temodar], rituximab, cytarabine) and was conducted by Alliance for Clinical Trials in Oncology, demonstrated superior PFS with ASCT; however, there was a notable difference in progressors (28% vs 11%, respectively; P = .05) during induction, which was the same treatment on both arms.

 There was no significant difference in OS. 

Overcoming Roadblocks for the Elderly Population

The improvement of treatment regimens for PCNSL has resulted in doubling of outcomes in patients over the past 2 decades, although survival in elderly patients has not changed since the 1970s.

 This is likely multifactorial. Older age has shown to be an independently adverse prognostic factor, regardless of treat-ment, and these patients, who account for a significant number of patients with PCNSL, typically have multiple comorbidities and cannot tolerate the aggressive regimens previously described.

Recent data from tertiary care institu-tions and experienced groups have shown that HD-MTX regimens can be delivered safely in elderly patients and can lead to clin-ically meaningful outcomes.

 In patients who are unable to safely tolerate and clear HD-MTX due to tentative renal function, such as many older patients, glucarpidase can be used to cleave MTX into nontoxic metab-olites eliminated by the liver.

There are ongoing clinical trials in several cancers, including PCNSL, to determine if glucarpi-dase can be used to safely deliver HD-MTX as an outpatient therapy to eliminate the long hospital stays required for continuous intra-venous hydration. Consolidation options in older patients are currently lacking.

Up to one-third of patients with PCNSL are refractory to first-line therapy, and approx-imately 50% have a recurrence in the first 2 years.

The management of relapsed or refrac-tory disease is challenging because of limited treatment options and factors such as age and further neurologic impairment. Recent insights into the pathophysiology of PCNSL have led to its recognition as a biologically distinct disease with targetable alterations and mutations.

B-cell receptor (BCR) has been identified as a key signaling pathway in PCNSL. Frequent genetic alterations of NF-κB and compo-nents of the toll-like receptor (TLR), such as 

, are seen in PCNSL in higher percentages (> 70%-89%) compared with the ABC subtype of systemic DLBCL.

 Deletions or mutations in TNFAIP3 associated with chromosome 6q loss have been noted, as have chromosome 18q gains with high BCL2 expression. Copy number amplifications at chromosome 9p24.1 associated with PD-L1/PD-L2 expression have been described, which may imply a role in immune evasion in PCNSL. These and other observations have led to several phase 1 and 2 clinical trials with novel targeted agents as well as immunotherapies (TABLE

Various Bruton tyrosine kinase (BTK) inhibitors, immunomodulatory drugs, checkpoint inhibitors, mTOR/PI3K inhibi-tors, and BCL2 inhibitors are being studied as monotherapies or in combination.26 The BTK inhibitor ibrutinib (Imbruvica) and the immunomodulatory drug lenalidomide (Revlimid) are included in the National Comprehensive Cancer Network guidelines as considerations for relapsed or refractory PCNSL based on the evidence of activ-ity.35 Although the responses with these agents are high—50% to 60%—the durability of the responses is under 6 months. CD19-directed chimeric antigen receptor T-cell therapy, which has shown remarkable activ-ity and long-term remission in relapsed or refractory systemic DLBCL, is being investi-gated in PCNSL.

The precise role of novel agents in PCNSL, including combinations and their introduc-tion in first-line treatment, is also under investigation. The agents hold tremendous promise for improving response rates and overall outcomes. Ongoing studies to enhance the knowledge of the unique biology of PCNSL—particularly mechanisms of resis-tance, role of circulating tumor DNA in CSF in defining minimal residual disease and its relevance to recurrence, and identification of predictive biomarkers—will be critical to designing effective therapeutic options.

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Articles

Primary central nervous system lymphoma is a rare and aggressive variant of extranodal non-Hodgkin lymphoma that occurs in the brain, spinal cord, cerebrospinal fluid, or eyes in the absence of systemic disease.

Lakshmi Nayak, MD

Articles

Dr Nayak on the Ongoing Investigation of Emavusertib Plus Ibrutinib in R/R PCNSL

Dr Nayak on the Investigation of Axi-Cel in CNS Lymphoma

Dr Nayak on the Identification of Primary CNS Lymphoma

Future of Care for PCNSL Relies on Adapting Personalized Approaches