Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study

Holte, Harald; Leppä, Sirpa; Björkholm, Magnus; Fluge, Øystein; Jyrkkiö, Sirkku; Delabie, Jan; Sundström, Christer; Karjalainen–Lindsberg, Marja-Liisa; Erlanson, Martin; Kolstad, Arne; Fosså, Alexander; Østenstad, Bjørn; Löfvenberg, Eva; Nordström, Marie; Janes, Rita; Pedersen, Lars Møller; Anderson, Harald; Jerkeman, Mats; Eriksson, Mikael

doi:10.1093/annonc/mds621

Cited by 102 publications

(93 citation statements)

References 42 publications

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“…6 The cohorts under study include patients with gene expression data from a Nordic phase II trial (dose-dense chemoimmunotherapy with central nervous system prophylaxis, n=38), 7 from the Cancer Genome Characterization Initiative (R-CHOP, n=92) and from the LLMPP (R-CHOP, n=233 and CHOP, n=181). Immunohistochemistry data were generated using the KP1 anti-human CD68 antibody and positive cells were counted manually.…”

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confidence: 99%

Tumor-associated macrophages in diffuse large B-cell lymphoma

2015

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confidence: 99%

Tumor-associated macrophages in diffuse large B-cell lymphoma

2015

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“…Several subsequent retrospective 68,76,77 and 2 prospective studies also support a potential benefit for high-dose systemic MTX in this setting. 78,79 However, these studies are limited by small numbers and nonrandomized and retrospective study designs, with the prospective studies using other CNS-penetrating agents in combination with MTX. There remains lack of consensus regarding a systemic MTX-dosing regimen, number of cycles, and whether IT prophylaxis has any role or not.…”

Section: How I Deliver Cns Prophylaxismentioning

confidence: 99%

“…Holte et al used dose-dense rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone delivered in 14-day cycles, followed by intensification with high-dose cytarabine and HD-MTX in 156 patients with DLBCL aged 18 to 65 years with age-adjusted IPI 2-3. 79 Apart from 1 dose of IT MTX on baseline lumbar puncture, IT chemotherapy prophylaxis was not given. CNS relapses occurred in 7 patients (4.4%), all within 6 months of study entry, again highlighting the need to provide some form of prophylaxis early during treatment.…”

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How I treat patients with aggressive lymphoma at high risk of CNS relapse

Chin

Cheah

2017

Blood

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Central nervous system (CNS) relapses are an uncommon yet devastating complication of non-Hodgkin lymphomas. The identification of patients at high risk of secondary CNS relapse is therefore paramount. Retrospective data indicate prophylactic CNS-directed therapies may reduce the risk of CNS involvement; however, no consensus exists about dose, timing, or route of therapy. In addition, prophylaxis is not without risk of treatment-related complications and morbidity. Here, we present a series of case vignettes highlighting our approach to common dilemmas encountered in routine clinical practice. We review the method of assessing CNS relapse risk, factors that increase the likelihood of relapse including histologic subtype, MYC rearrangement, protein expression, and extranodal involvement, and review our clinical practice based on available evidence in administering CNS-directed prophylaxis. (Blood. 2017;130(7):867-874) IntroductionNon-Hodgkin lymphomas are biologically and clinically diverse hematological malignancies. Treatment is influenced by patient fitness, disease biology, and tumor burden. Identifying patients at high risk of central nervous system (CNS) relapse is important as the outcome of secondary CNS lymphoma is poor. [1][2][3][4] Risk of CNS progression is influenced by histologic subtype and subtype-specific clinicopathologic features (eg, site of involvement, protein expression, or gene rearrangements). Patients with highly aggressive lymphomas (eg, lymphoblastic, Burkitt lymphoma) are at high risk and frontline protocols include CNS-directed prophylaxis. In contrast, indolent lymphomas rarely involve the CNS and CNS prophylaxis is not required. Between these extremes fall diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL) with MYC and BCL2 or BCL6 rearrangements, so-called "double-hit" lymphomas (HGBL-DH), and (nodal) peripheral T-cell lymphomas (PTCLs). The addition of rituximab has slightly reduced CNS relapse in DLBCL, probably through superior systemic control as there is negligible CNS penetration of the drug across the intact blood-brain barrier. 1,5 However, ;4% of unselected patients with DLBCL treated with prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-CHOP) experience CNS relapse, 6,7 and considerable efforts have been made to identify those at greatest risk. In this review, we will summarize our approach to this problem with case vignettes drawn from our practice. How I identify patients at increased risk for CNS relapseMany investigators have examined risk factors for CNS relapse, but studies have yielded inconsistent results, due to heterogeneity in patient populations, treatment, and/or limited sample size. [8][9][10][11][12][13][14][15][16] To address some of these limitations, Schmitz et al developed a 6-point score from 2164 patients treated on prospective German studies and validated in 1597 patients with DLBCL treated with R-CHOP in the British Columbia Cancer Agency (BCCA) Lymphoid Malignancies Database. 6 The components of the s...

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“…In all guidelines of the study period, CNS prophylaxis was recommended for patients with involvement of the testis or those with elevated lactate dehydrogenase (LDH) and >1 extranodal site. The guidelines specified CNS prophylaxis with intrathecal methotrexate injections with each cycle of R-CHO(E)P or highdose cytarabine and high-dose methotrexate (as extra cycles added to R-CHO(E)P or as part of hyper-CVAD/MA or R-B-NHL-BFM 04 (Holte et al, 2011;Lisfeld et al, 2013)). The national guidelines remained unchanged throughout the study period.…”

Section: Therapy Guidelines In Sweden 2007-2012mentioning

confidence: 99%

Chemotherapeutic intensity and survival differences in young patients with diffuse large B‐cell lymphoma: a Swedish Lymphoma Registry study

et al. 2016

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Summary Young patients with diffuse large B‐cell lymphoma (DLBCL) are variably treated with rituximab combined with cyclophosphamide‐doxorubicin‐vincristine‐prednisone (R‐CHOP), CHOP‐etoposide (R‐CHOEP), and anthracycline‐based regimens with the addition of high‐dose cytarabine/methotrexate (R‐HDA/M). Using the nationwide, population‐based Swedish Lymphoma Registry, we evaluated outcome, by treatment and Healthcare Region, in all 751 DLBCL patients aged ≤60 years without central nervous involvement, diagnosed in Sweden between 2007 and 2012. Overall survival was estimated using multivariate Cox analysis. In patients with age‐adjusted international prognostic index (aaIPI) ≥ 2, the 5‐year overall survival (OS) was 70%, 76% and 85% after R‐CHOP, R‐CHOEP and R‐HDA/M, respectively (P = 0·002); the corresponding estimates were 40%, 55%, and 92% in aaIPI = 3 (P = 0·014). There were large therapeutic differences between Sweden's six Healthcare Regions for aaIPI ≥ 2: three were “Moderate” (more R‐CHOP) and three “Intensive” (more R‐CHOEP and R‐HDA/M). Patients with aaIPI ≥ 2 who were treated in the Intensive Regions, showed better OS (P < 0·00005), particularly those with aaIPI = 3 (5‐year OS, 62% vs. 30%; P < 0·00005). There were no regional differences in therapy or survival in patients with aaIPI < 2. We conclude that in younger high‐risk patients, survival appears superior after more intensive therapy than R‐CHOP.

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Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study

Cited by 102 publications

References 42 publications

Tumor-associated macrophages in diffuse large B-cell lymphoma

Tumor-associated macrophages in diffuse large B-cell lymphoma

How I treat patients with aggressive lymphoma at high risk of CNS relapse

Chemotherapeutic intensity and survival differences in young patients with diffuse large B‐cell lymphoma: a Swedish Lymphoma Registry study

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