Central nervous system prophylaxis in mantle cell lymphoma

To the editor:

In their thorough review of mantle cell lymphoma (MCL),¹  Ghielmini and Zucca describe that central nervous system (CNS) disease involvement, albeit rare at presentation, has an incidence of 4% to 22% in relapsed patients. Nevertheless, they do not state their recommendations regarding prophylaxis to MCL patients. The National Comprehensive Cancer Network (www.nccn.org) guidelines for diffuse large B-cell (DLBCL) lymphoma recommend CNS prophylaxis with 4 to 8 doses of intrathecal methotrexate (MTX) and/or cytarabine for patients with aggressive lymphomas who have paranasal sinus, testicular, epidural, bone marrow, 2 extranodal site involvement, or HIV lymphomas. The guidelines for MCL patients further suggest lumbar puncture at diagnosis for patients with blastic variants or with neurologic symptoms, but do not state any recommendations for prophylactic treatment at either diagnosis or relapse. Because there are no definite guidelines, and most patients are not treated with CNS-penetrating agents such as high dose MTX/cytarabine regimens,¹  it is left to the physician's discretion whether to administer CNS prophylaxis or not. For instance, in the United Kingdom, one-third of hematologists administer prophylaxis to MCL patients and only in specific circumstances.²  Among the many reports of MCL in the literature, 4 concentrated their efforts on direct assessment of CNS involvement in MCL,^3-6  and all are retrospective (Table 1); therefore, the true incidence is unknown.

Interestingly, although most patients with CNS involvement develop symptoms at or after first relapse, not only the blastoid variant MCL had this propensity while having a higher risk. It might be argued that since most patients will succumb to their disease, which is rarely curable, and because CNS disease is only one part of a systemic relapse,³  there is limited application for primary prophylaxis. Nevertheless, in all reports, CNS disease was associated with worse overall survival. In addition, with the advent of newer agents and curative treatment attempts, patients may achieve more prolonged survival. It is controversial whether CNS prophylaxis for NHL can prevent CNS disease.⁷  In most MCL cohorts only a minority of patients received prophylaxis. Gill et al describe 10 patients who received prophylaxis with CNS-penetrating agents or intrathecal injections; none had developed CNS disease, compared with 4 of 52 not receiving such treatment.⁴  In contrast, Ferrer et al found no prophylactic advantage in patients receiving systemic high-dose MTX.³ 

It is the policy at our institution to provide CNS prophylaxis to those MCL patients with high-risk features, according to the NCCN guidelines for DLBCL. We use the addition of 2 high-dose MTX (> 3 gr/m²) courses if not included in the original chemotherapy protocol and 4 injections of intrathecal MTX. Given that the rate of CNS involvement at relapse may exceed one-quarter of patients, and more in those with blastoid variants, and the prospect of obtaining prolonged remissions with curative treatment attempts, we believe that CNS prophylaxis is warranted until further recommendations are prospectively investigated in clinical trials.