Page 40 - 2019_01-Haematologica-web

D. Qualls et al.
Two other retrospective studies evaluated high-dose methotrexate for CNS prophylaxis in DLBCL. In one Italian center, high-dose methotrexate (with or without intrathecal liposomal cytarabine at the discretion of the treating physician) was administered after completion of all cycles of R-CHOP for three or four cycles in patients deemed at high risk of CNS recurrence.66 These patients were then retrospectively compared to patients with high- risk features treated with no CNS prophylaxis. At a medi- an of 60 months, 12% of patients who did not receive pro- phylaxis had had a CNS relapse versus 2.5% of those who received prophylaxis (P=0.03), suggesting that CNS pro- phylaxis was beneficial. Of note, there were differences in risk factors between the two populations with more patients being defined as having high-risk disease due to advanced stage and elevated lactate dehydrogenase con- centration in the group that received no prophylaxis, while high-risk anatomic locations including testis, kidney and orbit were enriched in the prophylaxed population. Such differences in patient selection complicate the inter- pretation of all retrospective analyses, so that conclusions can be considered suggestive but not definitive. That said, a third retrospective analysis reported concordant results with lower rates of CNS relapse in patients treated with a
combination of high-dose intravenous methotrexate and intrathecal methotrexate compared to intrathecal methotrexate alone with a hazard ratio for CNS relapse at 3 years of 0.26 (95% confidence interval: 0.08 – 0.81) based on multivariate analysis.79
Two prospective trials have incorporated high-dose methotrexate and cytarabine, in addition to other CNS- active agents, for high-risk patients with DLBCL. A phase II trial of R-CODOX-M/IVAC (cyclophosphamide, vin- cristine, doxorubicin, methotrexate, ifosfamide, etopo- side, and cytarabine) was performed in patients with newly diagnosed DLBCL and an IPI score of ≥3.80 Among 96 patients with no CNS involvement at diagnosis, 41 had CNS-IPI scores of 2-3 (intermediate risk) and 55 had CNS- IPI scores of 4-6 (high risk); the rates of CNS relapse in these groups at 2 years were 0% and 6%, respectively, which are lower than might have been predicted without CNS-directed therapy, although the concomitant toxicity of these intensive regimens must be taken into account. The Nordic Lymphoma Study Group performed a phase II study in patients with high-risk DLBCL or grade 3 follicu- lar lymphoma, with age-adjusted IPI scores of 2-3.23 Treatment consisted of six cycles of R-CHOEP-14 (R- CHOP-14 plus etoposide) followed by cytarabine at 3000
Figure 2. Suggested approach to central nervous system risk stratification and prophylaxis in newly diagnosed diffuse large B-cell lymphoma. DLBCL: diffuse large B-cell lymphoma; CNS-IPI: Central Nervous System International Prognostic Index; DHL: double-hit lymphoma; COO: cell of origin; ABC: activated B-cell; DEL: double- expressing lymphoma; THL: triple-hit lymphoma; LP: lumbar puncture; MRI: magnetic resonance imaging; CNS: central nervous system; CSF: cerebrospinal fluid; MTX: methotrexate; CrCl: creatine clearance; HD-MTX: high-dose methotrexate; IT-MTX: intrathecal methotrexate.
30
haematologica | 2019; 104(1)