Primary Central Nervous System Lymphoma: Symptoms, Diagnosis, Treatment and New Therapies

The clinical presentation of PCNSL varies depending on the area affected by the disease. The most common manifestations include changes in behavior and personality, particularly because the frontal lobe, which is involved in approximately 40% of cases, is responsible for numerous cognitive and behavioral functions.

Symptoms related to increased intracranial pressure may also occur, including headache, nausea and vomiting, as well as focal neurological symptoms, such as:

• hemiplegia (paralysis of one side of the body);
• changes in sensation or motor function in one or more limbs;
• urinary incontinence, in some cases.

Unlike other central nervous system tumors, seizures are relatively uncommon, occurring in approximately 5% of patients.

“The variety of symptoms depends on the different areas of the central nervous system that may be involved,” explains Prof. Ferreri. “For this reason, the clinical presentation can vary considerably from patient to patient and may include cognitive and behavioral changes as well as focal neurological symptoms.”

A particularly important aspect is ocular involvement. In 15-20% of cases, the disease may initially develop in the eye. In these patients, visual disturbances characterized by the perception of small spots or moving objects in the field of vision, known as floaters, may be present several months before neurological symptoms appear.

Ocular involvement primarily affects the vitreous and the retina. In the vitreous, cancer cells are found in a liquid environment and can therefore move with movements of the head or eyes, whereas retinal lesions remain fixed.

The average age at diagnosis is gradually shifting toward 65-70 years, partly because the disease is now being diagnosed more frequently in older adults.

In the past, a biopsy might not have been performed in a very elderly patient with a brain lesion, particularly when no effective treatments were available to offer afterward. Today, the situation has changed: the availability of specific treatments has made an accurate diagnosis much more important and has led to a significant increase in biopsies in older patients as well, when their clinical condition allows.

“Advanced age alone should not be a reason to forgo diagnosis,” emphasizes the specialist. “Today, we have specific treatments available, and accurately identifying the nature of the lesion is essential in order to evaluate the most appropriate treatment.”

In most cases, the diagnosis is made through a brain biopsy, usually a stereotactic biopsy, which allows a tissue sample to be collected for histological and molecular analysis.

The procedure is generally well tolerated, but it is not without risks, including bleeding, particularly given the marked vascularity of lymphoma.

However, not all areas of the brain can be easily biopsied. The brainstem is a particularly delicate example, as it contains structures that are essential for controlling numerous neurological, respiratory and cardiovascular functions. In these situations, access to less invasive diagnostic tools becomes particularly important.

The Role of Cerebrospinal Fluid

In recent years, biomarkers in cerebrospinal fluid have been studied, including specific genetic mutations and interleukin-10.

These markers may help identify the disease with high sensitivity, exceeding 95% in some studies, and represent an important avenue toward a faster and less invasive diagnosis in selected patients.

Vitreous analysis can also help establish the diagnosis in patients with ocular involvement.

“The development of biomarkers in cerebrospinal fluid is one of the most interesting areas of research,” Prof. Ferreri notes. “The goal is to achieve an increasingly rapid and less invasive diagnosis in selected patients, particularly when brain biopsy presents specific difficulties or risks.”

First-line treatment is selected based on the patient’s general health, age and eligibility for autologous stem cell transplantation.

Treatment for Patients Eligible for Autologous Stem Cell Transplantation

For younger patients in good general health who are eligible for transplantation, treatment involves high-dose combination chemotherapy that includes methotrexate, a key drug because of its ability to reach the central nervous system.

One of the most widely used treatment regimens is MATRix, a combination developed at IRCCS Ospedale San Raffaele through international research collaboration.

In patients who respond to treatment, autologous stem cells are collected, followed by very high-dose chemotherapy, including thiotepa, and subsequent reinfusion of the stem cells.

With this approach, among patients who complete treatment and proceed to transplantation after achieving a response, the 7-year survival rate can reach 70-80%, indicating the possibility of achieving very long-lasting remissions.

“For patients who are able to undergo intensive treatment, the goal is not only to achieve a response to initial therapy, but also to consolidate that response over time,” explains the oncologist. “In this context, autologous transplantation represents a fundamental strategy.”

Treatment for Patients Not Eligible for Transplantation but Eligible for Chemotherapy

A second group includes patients who are not eligible for transplantation but are still able to tolerate chemotherapy. In these cases, less intensive treatments are used, after which radiation therapy or maintenance therapy, including orally administered medications, may be considered.

Radiation therapy is used more cautiously, particularly in older patients, because of the risk of neurotoxicity and potential effects on cognitive function.

Treatment for Patients Not Eligible for Either Transplantation or Chemotherapy

Finally, some more medically fragile patients are unable to tolerate either intensive chemotherapy strategies or transplantation. In these cases, more personalized and less toxic approaches are required.

In this context, one of the most important studies recently conducted in this disease was published in The Lancet last July, comparing 2 consolidation strategies following first-line chemoimmunotherapy.

The initial treatment is based on 4 drugs and was developed through a collaboration between Ospedale San Raffaele and University Hospital Freiburg in Germany. Prof. Ferreri is listed as co-first author of the study, whose authors also include Prof. Maurilio Ponzoni, Head of the hospital’s Pathology Laboratory, and Dr. Teresa Calimeri, oncologist at IRCCS Ospedale San Raffaele.

The study showed that, after achieving the best possible response, patients were randomized to receive 2 different consolidation strategies. Patients were assigned to:

• autologous stem cell transplantation, considered the conventional treatment;
• non-myeloablative R-DeVIC chemotherapy, a de-escalation strategy based on high-dose ifosfamide.

The study involved more than 300 patients and over 50 centers across 5 countries, making it the largest randomized phase III trial conducted to date in this disease.

Study Results

The results showed a significant advantage for patients who underwent autologous transplantation, with approximately 20% higher progression-free survival compared with the non-myeloablative strategy.

The findings therefore reinforce the role of autologous transplantation as a consolidation strategy in eligible patients and highlight the importance of using regimens that include thiotepa.

“These results strengthen the role of autologous transplantation in patients who are able to undergo the procedure,” Prof. Ferreri emphasizes. “The direct comparison between the 2 strategies provides important guidance when choosing consolidation treatment after initial therapy.”

The study results suggest that further investment in autologous transplantation is needed, while also seeking to extend this strategy to progressively older patients selected according to their general health.

However, the study also highlighted another important finding: non-myeloablative chemotherapy may represent an alternative for some patients who are unable to undergo transplantation, for example because an adequate number of stem cells cannot be collected or because infectious complications develop. It is a less intensive option that is not cross-resistant with previous treatments and may still provide a benefit for some of these patients.

“The non-myeloablative strategy may continue to play a role in patients who are unable to proceed to transplantation,” says the doctor, “providing a treatment alternative for those whose clinical condition or complications prevent them from undergoing intensive treatment.”

Another particularly significant finding concerns quality of life and cognitive function. Neuropsychological assessment of patients after a median follow-up of almost 4 years did not show significant deterioration in higher cognitive functionsattributable to the treatments being compared.

This is an important result given the risk of neurotoxicity associated with the therapies used to treat this disease.

Despite the progress made, much remains to be done, particularly for older patients and those who cannot undergo transplantation. Outcomes in this population are still far from optimal. Research is therefore focusing on 2 main objectives:

• making the diagnostic process faster and less invasive;
• identifying new drugs capable of improving the effectiveness of first-line treatment.

This is a particularly complex patient population: some patients cannot undergo transplantation because of hematologic toxicity, while the use of radiation therapy may be limited by the risk of neurotoxicity.

It is therefore essential to develop new strategies based on biologic drugs and targeted therapies, with the aim of improving treatment outcomes while maintaining a good tolerability profile.

“The main challenge in the coming years will be to improve treatment options for older patients and those who are not eligible for transplantation,” Prof. Ferreri concludes. “We need to develop treatments that are more effective but, at the same time, better tolerated, with particular attention to preserving neurological and cognitive function.”