Pharmacology Consult

Intrathecal rituximab offers new approach to treatment of leptomeningeal malignancy

With the advent of new technology and therapies, patients with cancer are living longer. However, improved survival rates bring higher rates of relapse, particularly central nervous system relapse. The focus of this article is to review central nervous system complications associated with solid tumors and lymphoma, current treatment strategies, and a new approach to treatment.

Leptomeningeal malignancy is the seeding of malignant cancer cells to the leptomeninges. Signs and symptoms usually consist of headache and altered mental status, including cognitive impairment and confusion. Currently, leptomeningeal malignancy is diagnosed in about 5% of patients with cancer. The diagnosis of leptomeningeal malignancy is occurring more frequently and can be attributed to advances in imaging, improved management of systemic disease and increased OS. Lymphoma and solid tumor malignancies, including small cell lung cancer, breast cancer and melanoma, are associated with the highest incidence of leptomeningeal involvement.

Current treatment strategies

Without treatment, survival of patients with leptomeningeal malignancy is usually limited to several weeks. Current treatment strategies offer some improvement in length of survival, upward of 3 to 6 months. Guidelines from the National Comprehensive Cancer Network stratify patients into one of two risk groups. Patients deemed poor risk include those with bulky central nervous system (CNS) disease, extensive neurologic deficits or widely disseminated disease lacking further treatment options. Those considered good risk include patients with minimal systemic disease and minor neurologic impairment.

Treatment for leptomeningeal malignancy with patients at poor risk most often consists of supportive care and palliative measures. Conventional treatment modalities for the management of patients in the good risk group include systemic chemotherapy and radiation therapy. Intrathecal chemotherapy has also become a mainstay in the treatment of leptomeningeal malignancy with traditional chemotherapy agents, including methotrexate, cytarabine and thiotepa. Unfortunately, response to these standard therapies remains low.

Tiffany Capouch, PharmD
Tiffany Capouch

Poor response to systemic chemotherapy can be explained for several reasons, the first being the blood-brain barrier. The CNS can act as a safe haven for tumor cells because of the inability of systemic chemotherapy to penetrate the barrier. Systemic doses of chemotherapy required to achieve adequate concentrations at the site of leptomeningeal involvement are associated with high rates of adverse events, further explaining meager response. In addition, many of the agents used for systemic chemotherapy are composed of molecules that are simply too large to pass through the blood-brain barrier into the CNS. With systemic chemotherapy providing little benefit in instances of leptomeningeal malignancy, attention has turned to a different treatment avenue — intrathecal administration.

New treatment strategy

The use of the monoclonal antibody rituximab (Rituxan; Genentech, Biogen Idec) has gained favor in the treatment of CD20+ lymphoproliferative malignancies. IV administration has demonstrated an increase in survival in patients with systemic disease. Unfortunately, however, this route of administration has not been shown to decrease the risk for disease occurrence in the CNS. This outcome is likely related to the inability of rituximab to adequately cross the blood-brain barrier.

The agent has consistently failed to achieve adequate concentrations in the cerebrospinal fluid because of poor penetration. It has been demonstrated that the concentration of rituximab in the cerebrospinal fluid after IV administration is equal to approximately 0.1% of serum levels. Rituximab’s mechanism of action, combined with its poor ability to penetrate the blood-brain barrier, has prompted research into use of this agent for intrathecal administration.

To date, there have been seven case reports published regarding intrathecal rituximab use in CNS lymphoma. In these cases, the dose of rituximab ranged from 10 mg to 40 mg. An initial dose of 10 mg was used most often and gradually escalated to clinical response or patient tolerance, whichever occurred first. Of the seven patients, all showed cytologic response, and four had improvement in symptoms, including resolution of headaches, seizures and cognitive function.

Of note, one case reported progression of CNS disease. Patient survival spanned from 4 months to more than 3.5 years. The most common adverse effects associated with therapy included headache, pain, leg weakness and cramps. Infusion-related reactions were reported with the 40-mg doses but did not produce any residual adverse effects.

In 2007, a phase 1 study was published investigating the use of intrathecal rituximab with goals of defining the agent’s safety, efficacy and pharmacokinetic profile. The study population included 10 patients, each of whom was enrolled into one of three rituximab dose cohorts: 10 mg, 25 mg or 50 mg. Doses were administered diluted in normal saline (NaCl 0.9%) or undiluted as straight drug during a period of 1 minute to 5 minutes.

Each patient received premedication with acetaminophen, diphenhydramine and cimetidine or famotidine 30 minutes before rituximab administration. Also, just before rituximab injection, a minimum of 5 mL of cerebrospinal fluid was removed. Of the eight patients who received 10- or 20-mg doses, none demonstrated signs or symptoms of major toxicity. Both patients who received 50-mg doses experienced major toxicity, including grade 3 hypertension, chest pain, tachypnea, diplopia and nausea/vomiting. Resolution of symptoms occurred within 20 minutes with appropriate supportive care.

Of the 10 patients, six demonstrated cytologic responses; four of those achieved a complete response. Patient survival ranged from 1.1 weeks to upward of 134 weeks. Cerebrospinal fluid concentrations 1 hour after dose were 214 mcg/mL and 472 mcg/mL for 10-mg and 25-mg doses, respectively. These concentrations achieved in the cerebrospinal fluid are similar to those serum concentrations obtained after systemic rituximab administration.

After the dose, concentrations of rituximab declined rapidly; a half-life of 34.9 hours was reported for the 25-mg dose. As previously demonstrated with systemic rituximab therapy, successful response appears to be correlated with sustained concentrations.

Based on this phase 1 study and the previously mentioned case reports, intrathecal rituximab shows potential for treatment of leptomeningeal CD20-associated lymphoproliferative malignancies. Although instances of toxicity have been described in all cases, most are associated with doses of 40 mg or higher and resolve with appropriate medical management. In all reports, doses of intrathecal rituximab were delivered via lumber puncture or use of an Ommaya reservoir.

Conclusion

With the use of conventional therapies, the prognosis for leptomeningeal lymphomatosis is dismal. The prime suspect in preventing systemic therapy from reaching the site of leptomeningeal disease is the blood-brain barrier. To overcome this barrier, drug administration directly to the site of CNS involvement is being explored. Existing data suggest that the use of intrathecal rituximab may be safe and effective. However, more studies are needed to establish optimal dose, frequency and duration of therapy.

Tiffany Capouch, PharmD, is an oncology pharmacy specialty PGY2 resident at the University of Minnesota Medical Center, Minneapolis.

For more information:

  • Antonini G. J Neurooncol. 2007;81:197-199.
  • Perissinotti AJ. Ann Pharmacother. 2010;44:1633-1640.
  • Rubenstein JL. J Clin Oncol. 2007;25:1350-1356.
  • Villela L. Anticancer Drugs. 2008;19:917-920.

With the advent of new technology and therapies, patients with cancer are living longer. However, improved survival rates bring higher rates of relapse, particularly central nervous system relapse. The focus of this article is to review central nervous system complications associated with solid tumors and lymphoma, current treatment strategies, and a new approach to treatment.

Leptomeningeal malignancy is the seeding of malignant cancer cells to the leptomeninges. Signs and symptoms usually consist of headache and altered mental status, including cognitive impairment and confusion. Currently, leptomeningeal malignancy is diagnosed in about 5% of patients with cancer. The diagnosis of leptomeningeal malignancy is occurring more frequently and can be attributed to advances in imaging, improved management of systemic disease and increased OS. Lymphoma and solid tumor malignancies, including small cell lung cancer, breast cancer and melanoma, are associated with the highest incidence of leptomeningeal involvement.

Current treatment strategies

Without treatment, survival of patients with leptomeningeal malignancy is usually limited to several weeks. Current treatment strategies offer some improvement in length of survival, upward of 3 to 6 months. Guidelines from the National Comprehensive Cancer Network stratify patients into one of two risk groups. Patients deemed poor risk include those with bulky central nervous system (CNS) disease, extensive neurologic deficits or widely disseminated disease lacking further treatment options. Those considered good risk include patients with minimal systemic disease and minor neurologic impairment.

Treatment for leptomeningeal malignancy with patients at poor risk most often consists of supportive care and palliative measures. Conventional treatment modalities for the management of patients in the good risk group include systemic chemotherapy and radiation therapy. Intrathecal chemotherapy has also become a mainstay in the treatment of leptomeningeal malignancy with traditional chemotherapy agents, including methotrexate, cytarabine and thiotepa. Unfortunately, response to these standard therapies remains low.

Tiffany Capouch, PharmD
Tiffany Capouch

Poor response to systemic chemotherapy can be explained for several reasons, the first being the blood-brain barrier. The CNS can act as a safe haven for tumor cells because of the inability of systemic chemotherapy to penetrate the barrier. Systemic doses of chemotherapy required to achieve adequate concentrations at the site of leptomeningeal involvement are associated with high rates of adverse events, further explaining meager response. In addition, many of the agents used for systemic chemotherapy are composed of molecules that are simply too large to pass through the blood-brain barrier into the CNS. With systemic chemotherapy providing little benefit in instances of leptomeningeal malignancy, attention has turned to a different treatment avenue — intrathecal administration.

New treatment strategy

The use of the monoclonal antibody rituximab (Rituxan; Genentech, Biogen Idec) has gained favor in the treatment of CD20+ lymphoproliferative malignancies. IV administration has demonstrated an increase in survival in patients with systemic disease. Unfortunately, however, this route of administration has not been shown to decrease the risk for disease occurrence in the CNS. This outcome is likely related to the inability of rituximab to adequately cross the blood-brain barrier.

The agent has consistently failed to achieve adequate concentrations in the cerebrospinal fluid because of poor penetration. It has been demonstrated that the concentration of rituximab in the cerebrospinal fluid after IV administration is equal to approximately 0.1% of serum levels. Rituximab’s mechanism of action, combined with its poor ability to penetrate the blood-brain barrier, has prompted research into use of this agent for intrathecal administration.

To date, there have been seven case reports published regarding intrathecal rituximab use in CNS lymphoma. In these cases, the dose of rituximab ranged from 10 mg to 40 mg. An initial dose of 10 mg was used most often and gradually escalated to clinical response or patient tolerance, whichever occurred first. Of the seven patients, all showed cytologic response, and four had improvement in symptoms, including resolution of headaches, seizures and cognitive function.

Of note, one case reported progression of CNS disease. Patient survival spanned from 4 months to more than 3.5 years. The most common adverse effects associated with therapy included headache, pain, leg weakness and cramps. Infusion-related reactions were reported with the 40-mg doses but did not produce any residual adverse effects.

In 2007, a phase 1 study was published investigating the use of intrathecal rituximab with goals of defining the agent’s safety, efficacy and pharmacokinetic profile. The study population included 10 patients, each of whom was enrolled into one of three rituximab dose cohorts: 10 mg, 25 mg or 50 mg. Doses were administered diluted in normal saline (NaCl 0.9%) or undiluted as straight drug during a period of 1 minute to 5 minutes.

Each patient received premedication with acetaminophen, diphenhydramine and cimetidine or famotidine 30 minutes before rituximab administration. Also, just before rituximab injection, a minimum of 5 mL of cerebrospinal fluid was removed. Of the eight patients who received 10- or 20-mg doses, none demonstrated signs or symptoms of major toxicity. Both patients who received 50-mg doses experienced major toxicity, including grade 3 hypertension, chest pain, tachypnea, diplopia and nausea/vomiting. Resolution of symptoms occurred within 20 minutes with appropriate supportive care.

Of the 10 patients, six demonstrated cytologic responses; four of those achieved a complete response. Patient survival ranged from 1.1 weeks to upward of 134 weeks. Cerebrospinal fluid concentrations 1 hour after dose were 214 mcg/mL and 472 mcg/mL for 10-mg and 25-mg doses, respectively. These concentrations achieved in the cerebrospinal fluid are similar to those serum concentrations obtained after systemic rituximab administration.

After the dose, concentrations of rituximab declined rapidly; a half-life of 34.9 hours was reported for the 25-mg dose. As previously demonstrated with systemic rituximab therapy, successful response appears to be correlated with sustained concentrations.

Based on this phase 1 study and the previously mentioned case reports, intrathecal rituximab shows potential for treatment of leptomeningeal CD20-associated lymphoproliferative malignancies. Although instances of toxicity have been described in all cases, most are associated with doses of 40 mg or higher and resolve with appropriate medical management. In all reports, doses of intrathecal rituximab were delivered via lumber puncture or use of an Ommaya reservoir.

Conclusion

With the use of conventional therapies, the prognosis for leptomeningeal lymphomatosis is dismal. The prime suspect in preventing systemic therapy from reaching the site of leptomeningeal disease is the blood-brain barrier. To overcome this barrier, drug administration directly to the site of CNS involvement is being explored. Existing data suggest that the use of intrathecal rituximab may be safe and effective. However, more studies are needed to establish optimal dose, frequency and duration of therapy.

Tiffany Capouch, PharmD, is an oncology pharmacy specialty PGY2 resident at the University of Minnesota Medical Center, Minneapolis.

For more information:

  • Antonini G. J Neurooncol. 2007;81:197-199.
  • Perissinotti AJ. Ann Pharmacother. 2010;44:1633-1640.
  • Rubenstein JL. J Clin Oncol. 2007;25:1350-1356.
  • Villela L. Anticancer Drugs. 2008;19:917-920.