Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients

Wilson, Matthew R.; Eyre, Toby A.; Kirkwood, Amy A.; Doo, Nicole Wong; Soussain, Carole; Choquet, Sylvain; Martínez‐Calle, Nicolás; Preston, Gavin; Ahearne, Matthew J.; Schorb, Elisabeth; Moles-Moreau, Marie-Pierre; Ku, Matthew; Rusconi, Chiara; Khwaja, Jahanzaib; Narkhede, Mayur; Lewis, K.L.; Calimeri, Teresa; Durot, Éric; Renaud, Loïc; Øvlisen, Andreas Kiesbye; McIlroy, Graham; Ebsworth, Timothy; Elliot, Johnathon; Santarsieri, Anna; Ricard, Laure; Shah, Nimish; Liu, Qin; Zayac, Adam; Vassallo, Francesco; Lebras, Laure; Roulin, Louise; Lombion, Naelle; Manos, Kate; Fernandez, Ruben; Hamad, Nada; López‐García, Alberto; O’Mahony, Deirdre; Gounder, Pav; Forgeard, Nathalie; Lees, Charlotte; Agbetiafa, Kossi; Struessmann, Tim; Htut, Thura Win; Clavert, Aline; Scott, Hamish; Guidetti, Anna; Barlow, Brett; Tchernonog, Emmanuelle; Smith, Jeffery; Miall, Fiona; Fox, Christopher P.; Cheah, Chan Yoon; El‐Galaly, Tarec Christoffer; Ferreri, Andrés J.M.; Cwynarski, Kate; McKay, Pam

doi:10.1182/blood.2021014506

Cited by 54 publications

(55 citation statements)

References 34 publications

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“…High-dose methotrexate at various doses during or following chemoimmunotherapy was not associated with a significant reduction in CNS relapse (8•4% with high-dose methotrexate vs 9•1% without high-dose methotrexate, p=0•1). 50 Furthermore, in a retro spective cohort of 1384 patients who all received high-dose methotrexate, 3-year CNS relapse risk was 9•1% in 600 patients with DLBCL and CNS-IPI scores were 4-6, 23 remarkably similar to the cohorts examined in the original CNS-IPI development and validation cohorts (10•2%) where minimal CNS prophylaxis was used.…”

Section: Agents Used and Evidence Basementioning

confidence: 64%

“…A recent large retrospective study addressed the question of high-dose methotrexate timing, comparing patients receiving high-dose methotrexate delivered either intercalated (n=749) or at end of R-CHOP (n=635). 23 Delays to R-CHOP of 7 days or more were significantly increased with intercalated high-dose methotrexate versus delivery at the end of R-CHOP, with 20% of intercalated high-dose methotrexate treatments associated with a delay to subsequent R-CHOP. There was no difference in CNS relapse rate between the groups, including on multivariable analyses and when restricting analyses to the highest-risk patients.…”

Section: Reviewmentioning

confidence: 92%

“…Retrospective real-world studies of patients with secondary CNS lymphoma receiving heterogeneous treatments have reported median overall survival of approximately 6-12 months (appendix p 1). [21][22][23][24]…”

Section: Secondary Cns Lymphoma Outcomesmentioning

confidence: 99%

“…There was no difference in CNS relapse rate between the groups, including on multivariable analyses and when restricting analyses to the highest-risk patients. Overall, intercalated high-dose methotrexate is associated with R-CHOP interruption and delay, 23,57 compromising delivery and possibly the effectiveness of R-CHOP. Accepting the limitations of retrospective data, from which these results on high-dose methotrexate originate, results from this study support an end-of-R-CHOP delivery.…”

Section: Reviewmentioning

confidence: 99%

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CNS prophylaxis for diffuse large B-cell lymphoma

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Savage

Cheah

et al. 2022

The Lancet Oncology

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Section: Agents Used and Evidence Basementioning

confidence: 64%

Section: Reviewmentioning

confidence: 92%

Section: Secondary Cns Lymphoma Outcomesmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

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CNS prophylaxis for diffuse large B-cell lymphoma

Eyre

Savage

Cheah

et al. 2022

The Lancet Oncology

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“…cytarabine, ifosfamide, etoposide) crossing the blood-brain barrier (BBB) seemed more promising (7,9). However, randomized studies comparing prophylactic strategies have not been reported and more recent analyses shed doubts if IV HD MTX is more effective than IT MTX or has any preventive effect at all (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Central nervous system relapse in younger patients with diffuse large B-cell lymphoma - a LYSA and GLA/ DSHNHL analysis

Thiéblemont

Altmann

Frontzek

et al. 2022

Preprint

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The majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with immunochemotherapy comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients suffering progression or relapse in the central nervous system (CNS) face dismal outcomes. The impact of more aggressive regimens used in front-line therapy has not systematically been investigated in this context. To this end, we analyzed a large cohort of 2203 younger DLBCL patients treated on ten German and French prospective phase II and III trials following first-line therapy with R-CHOP, R-CHOEP (R-CHOP + etoposide), dose-escalated R-CHOEP followed by repetitive stem cell transplantation (R-MegaCHOEP), or rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycine, prednisone (R-ACVBP) followed by consolidation including multiple drugs crossing the blood-brain-barrier (BBB). DLBCL patients with age-adjusted International Prognostic Index (aaIPI) of 0–1 showed very low cumulative incidence (CI) rates of CNS relapse regardless of first-line therapy and CNS prophylaxis (3-year CI 0% − 1%). Younger high-risk patients with aaIPI of 2–3 had 3-year CI rates of 1.6% and 4% after R-ACVBP plus consolidation or R-(Mega)CHO(E)P, respectively (Hazard Ratio 2.4 (95% confidence interval: 0.8–7.4), p = 0.118). Thus, for younger high-risk patients, front-line regimens incorporating multiple agents crossing the BBB may reduce often fatal CNS relapse.

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Diffuse large B‐cell lymphoma at risk of secondary CNS involvement: The inefficacy of intravenous high‐dose methotrexate CNS prophylaxis and the importance of baseline cerebrospinal fluid analysis

Bennett,

Ruskova,

Coomarasamy

et al. 2023

American J Hematol

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High-dose intravenous methotrexate (HD-MTX) CNS prophylaxis in high-risk diffuse large B cell lymphoma (DLBCL) remains controversial. We describe real-world CNS relapse incidence following baseline cerebrospinal fluid (CSF) analysis to exclude asymptomatic leptomeningeal involvement in newly diagnosed high-risk DLBCL patients with versus without single-route HD-MTX CNS prophylaxis. Consecutively diagnosed high-risk systemic DLBCL patients without leptomeningeal involvement by CSF analysis (noCNS) were identified retrospectively. Five-year CNS relapse incidence and survival outcomes were examined, as stratified by receipt of HD-MTX prophylaxis. Secondary analysis of survival outcomes in patients with synchronous leptomeningeal involvement (CNSinv) by CSF analysis at diagnosis were compared with the noCNS group. No significant difference in 5-year CNS relapse incidence was observed following HD-MTX prophylaxis versus no prophylaxis (total n = 445) despite similar CNS-IPI risk; 6.2% versus 5.6%, adjusted HR 1.08 (95% CI 0.41-2.85), p = .88; nor in 5-year progression free survival (PFS) or overall survival (OS) risk. Of CNSinv patients, 93.3% had ≥1 extranodal site. Increased CNS relapse/progression risk (5-year risk; HR 10.7 [95% CI 5.35-21.37], p < .0001) and inferior PFS and OS were observed in CNSinv versus all noCNS patients. The CNSinv group had superior OS compared with noCNS patients who later experienced CNS relapse (HR 0.55, p = .052). HD-MTX prophylaxis does not reduce CNS relapse risk in high-risk systemic DLBCL without leptomeningeal involvement by CSF analysis at diagnosis. Asymptomatic patients with synchronous leptomeningeal involvement on baseline CSF examination are at increased risk of further CNS disease events and inferior survival compared to patients without CSF involvement. | BACKGROUNDCentral nervous system (CNS) involvement is a devastating presentation of diffuse large B-cell lymphoma (DLBCL) with historically dismal outcomes. Screening high-risk asymptomatic patients for leptomeningeal involvement at diagnosis is extremely important given the propensity for occult cases to present with early CNS relapse with high mortality risk. 1 There is no standard of care therapy for such patients. [2][3][4][5][6][7][8][9][10]

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Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients

Cited by 54 publications

References 34 publications

CNS prophylaxis for diffuse large B-cell lymphoma

CNS prophylaxis for diffuse large B-cell lymphoma

Central nervous system relapse in younger patients with diffuse large B-cell lymphoma - a LYSA and GLA/ DSHNHL analysis

Diffuse large B‐cell lymphoma at risk of secondary CNS involvement: The inefficacy of intravenous high‐dose methotrexate CNS prophylaxis and the importance of baseline cerebrospinal fluid analysis

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