THREE-HOUR INFUSION OF METHOTREXATE AT 3 g/m2 SIGNIFICANTLY REDUCES CNS RELAPSES AND IMPROVES SURVIVAL IN PATIENTS WITH LARGE B-CELL LYMPHOMAS AND INCREASED CNS RISK
A. J. M. Ferreri, F. Erbella, P. Angelillo, M. V. Ponti, L. Saliani, L. Pecciarini, L. Bongiovanni, T. Calimeri, A. Nonis, M. G. Cangi, F. Marino, E. Flospergher, G. Cassanello, P. Fiore, F. Palumbo, M. Ponzoni
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引用次数: 0
Abstract
Background: A few recent studies questioned the effectiveness of high-dose methotrexate (MTX) in preventing CNS relapse in large B-cell lymphomas (LBCL); however, they suffer from biases, such as unbalanced distribution of patients (pts) with high-risk extranodal disease and lack of complete information on MTX dosing schedules and CNS events. We reviewed a large, single-centre cohort of LBCL pts treated with uniform CNS-directed MTX dosing schedule, aiming to demonstrate its favourable effect on CNS recurrence and survival in pts with high CNS risk, as defined by recent consensus criteria (Eyre T, et al., Lancet Oncol 2022).
Methods: We reviewed 501 LBCL pts treated from 2002 to 2021, focusing on those who achieved complete metabolic remission (CMR) after upfront RCHOP or similar. Pts at high CNS risk, as defined by our institution’s criteria, received 2 (stage I-II) or 3 (advanced stage) doses of MTX (3 g/m2 over 3 hours, preceded by a fast bolus) after RCHOP. Histological specimens were reviewed, diagnoses updated according to the latest WHO/ICC classifications, and CNS risk reassessed using recent consensus criteria (CNS-IPI ≥ 4, ≥ 3 extranodal sites, or involvement of the testis, kidney, adrenal gland, or breast). MTX’s effect on CNS recurrence was assessed using Gray’s test, treating other events (systemic recurrence, unrelated death) as competing risks. MTX’s impact on PFS and OS was also assessed.
Results: 344 pts in CMR after RCHOP or similar were considered. CNS risk according to recent criteria was low in 231 (66%) pts and high in 113 (33%); MTX was given to 17 (7%) and 49 (43%) pts, respectively. After a median follow-up of 75 months (IQR 54–102), CNS relapse occurred in 13 (4%) pts, always as isolated site: brain (10), meninges (2), and cranial nerves (1). Among low-risk pts, CNS relapse rate was 2% (4/214) without MTX and 0% (0/17) with MTX. In high-risk pts, this rate was 14% (9/64) without MTX and 0% (0/49) with MTX, yielding a 4-year cumulative CNS relapse rate of 18% and 0%, respectively (p = 0.003). The most notable MTX benefit was seen in 62 pts with involvement of testes, kidneys, or adrenal gland, where CNS relapse rate dropped from 23% (7/31) to 0% (0/31) (p = 0.01), and in 66 pts with ≥ 3 extranodal sites, where rate dropped from 13% (5/38) to 0% (0/28) (p = 0.06). MTX also was associated with improved PFS and OS in the 113 high-risk pts (independent in multivariable analysis). In these pts, also event distribution suggested MTX’s role in prophylaxis: 8 (12%) unrelated deaths, 13 (20%) systemic relapses, and 9 (14%) CNS relapses occurred in the 64 pts treated without MTX, whereas 4 (8%) unrelated deaths, and 9 (18%) systemic relapses, with no CNS relapses, occurred in the 49 treated with MTX.
Conclusion: MTX (3 g/m2 over 3 hs) significantly reduces CNS relapses and improves PFS and OS in LBCL pts with CNS-IPI ≥ 4, ≥ 3 extranodal sites, or involvement of testis, kidney, adrenal gland, or breast who achieve CMR after RCHOP or similar.
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Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged:
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-Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies
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Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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