Abstract

Introduction: Patients (pts) with diffuse large B cell lymphoma (DLBCL) and high International Prognostic Index (IPI) or extra-nodal localization are at a higher risk for relapse with central nervous system (CNS) involvement. The current policy at the Rambam Health Care Campus (Haifa, Israel) is to give DLBCL pts 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) together with 4 doses of intrathecal (IT) methotrexate (MTX), which may be followed by 2 additional cycles of an intermediate dose (3 g/m2) of intravenous MTX (ID-MTX). The present study aimed to compare the outcome of DLBCL pts with risk factors for CNS relapse who did or did not receive prophylaxis with ID-MTX.

Methods: We retrospectively evaluated a cohort of DLBCL pts treated at Rambam between the years 1991 and 2012. Overall survival (OS), progression-free survival (PFS) and CNS involvement at relapse were estimated in 203 of 355 pts [96 females, 107 males; median age 59 (range18-90) years]. The study included all pts with the primary diagnosis of DLBCL and risk factors for CNS relapse, i.e., Waldeyer ring (5%), breast (2%), testicular (3%), orbital (1%) involvement, bone marrow involvement (25%), stage IV disease (63%), LDH > normal (68%), ≥1 extra-nodal site (26%), IPI ≥3 (41%). Ten percent of pts had stage I-IE disease, 15% - stage II-IIE, 12% - stage III, 63% - stage IV, 38% had B symptoms. Pts with CNS involvement at diagnosis were excluded from the study.

Results: One hundred and fifty patients (74%) were treated with R-CHOP. In this group, 40% of pts with IPI=0/1, 29% with IPI=2 and 47% with IPI ≥3 received ID-MTX prophylaxis. Sixty four pts received ID-MTX (32%), 14 pts (7%) received IT MTX only, 125 pts had no prophylaxis (62%). At a median follow-up of 92 months, 5% of pts had CNS relapse with no difference in incidence between the study groups. Pts with IPI≥3 treated with ID-MTX had a reduced overall relapse rate and significantly better PFS and OS (table 1).

Conclusion: The addition of 2 cycles of ID-MTX to the R-CHOP regimen improved both PFS and OS of DLBCL pts with IPI≥3. A randomized controlled study is warranted to provide stronger evidence.

Table 1.
All patients 
 Pts
No. 
PFS
*HR 95% CI OS
#HR 95% CI 
ID-MTX 65 60    88  
IT MTX 15 56 0.09 1.92 0.9-4.1 0.008 43 3.27 1.4-7.8 
No prophylaxis 123 42 0.04 1.58 1.0-2.49 0.002 51 2.49 1.4-4.4 
R-CHOP Data 
IPI≥3
no prophylaxis 
35 20    26  
IPI≥3 +ID-MTX 31 58 0.004 0.38 0.29-0.85 0.001 67 0.29 0.14-0.6 
All patients 
 Pts
No. 
PFS
*HR 95% CI OS
#HR 95% CI 
ID-MTX 65 60    88  
IT MTX 15 56 0.09 1.92 0.9-4.1 0.008 43 3.27 1.4-7.8 
No prophylaxis 123 42 0.04 1.58 1.0-2.49 0.002 51 2.49 1.4-4.4 
R-CHOP Data 
IPI≥3
no prophylaxis 
35 20    26  
IPI≥3 +ID-MTX 31 58 0.004 0.38 0.29-0.85 0.001 67 0.29 0.14-0.6 

No.: number; *HR: hazard ratio for progression; #HR for mortality; CI: confidential interval

Disclosures

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.