Dose-Dense Chemoimmunotherapy Including Early CNS Prophylaxis for High-Risk DLBCL. -Final Analysis from a Nordic Phase II Study (the CHIC trial)
Bibliographic record
Abstract
Abstract Introduction: Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of early central nervous system (CNS) progression is high. Here we present the final results from a Nordic phase II study, where dose-dense chemoimmunotherapy including early systemic CNS prophylaxis with high dose methotrexate (HD-Mtx), further intensified by intrathecally (IT) administered liposomal cytosine arabinoside (AraC), was given. Patients and methods: Inclusion criteria were age 18-65 years, de novo DLBCL or grade 3B follicular lymphoma without clinical, radiological or cytological signs of CNS involvement, age adjusted IPI 2-3, WHO performance score 0-3, and/or anatomical sites related to increased risk for CNS recurrence (e.g. testis, facial sinuses, orbita). Treatment consisted of two courses of HD-Mtx in combination with R-CHOP14, followed by four courses of R-CHOEP14 and one course of R-HD-AraC. Liposomal AraC was administered IT at courses 1, 3 and 5 (omitted during a period of production halt). Primary end points were failure free survival (FFS; disease progression, discontinuation of protocolled therapy due to toxicity, death from any cause) and CNS progression rate at 18 months. Among the secondary endpoints were the identification of biological risk factors for high risk disease and prognostic role of cerebrospinal fluid (CSF) cytology-/flow cytometry (FC)+for CNS recurrence. Results: Of the accrued 143 patients, 140 met the inclusion criteria and were evaluable for baseline characteristics and primary endpoints. Of these, 132 had a complete set of treatment data. The male/female ratio was 1.7 and the median age 56 years (range 20-64). The majority of the patients had DLBCL (96%), advanced clinical stage (93%), elevated LDH (91%), more than one extranodal site (73%), and B-symptoms (64%). A bulky lesion (>10 cm) was present in 37% of the patients and 11 CSF samples (8%) were FC+. Most patients (n=127, 96%) received a full treatment schedule. Liposomal AraC was given to 81 (61%) and radiotherapy to 39 (30%) patients. Grade 4 infections were observed in 12% of the patients. The frequency of grade 3-4 mucositis as well as gastrointestinal toxicity was 20%, and of grade 3 arachnoiditis 2,5%. Three toxic deaths were observed. In addition, three patients developed AML/MDS and one PML. At the end of treatment, CR/CRu, PR and PD rates were 79%, 17% and 3%, respectively. Of the 120 patients who underwent PET-CT, 92 (77%) achieved a metabolic CR (Deauville score (DS) 1-3). Three patients had primary refractory disease. At a median follow-up of 30 months, additional 14 patients had relapsed, three of them in the CNS (only one had a pre-therapeutic FC+ CSF), and 15 had died. FFS, PFS, OS and CNS progression rates at 30 months were 80%, 83%, 90%, and 2.4%, respectively. PET positivity (DS 4-5) at the end of treatment (p=0.019) and BCL2 expression (p=0.049) were associated with increased risk of progression, whereas other factors, such as molecular subtype (GC versus non-GC), Ki-67 score (≥70%), aaIPI group (2 versus 3), number of extranodal sites, FC-based CSF positivity, and treatment with liposomal AraC did not seem to have significant impact on outcome. Conclusions: Safety profile and final outcome results of the Nordic CHIC trial indicate high response rates, favorable survival, low number of CNS recurrences and manageable toxicity as a result of this CNS targeted intensive therapy schedule. PET response at the end of therapy and selected biological factors identify patients at high risk of progression. Disclosures Leppa: Roche: Honoraria, Other: Travel expenses, Research Funding; Janssen: Research Funding; Bayer: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Other: Travel expenses; CTI Life Sciences: Honoraria; Merck: Other: Travel expenses. Joergensen:Amgen: Research Funding; Mundipharma: Research Funding. Mannisto:SOBI: Honoraria; Pfizer: Honoraria; Gilead: Other: Travel expenses; Celgene: Other: Travel expenses; Novartis: Other: Travel expenses; Amgen: Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Roche: Honoraria, Other: Travel expenses. Jerkeman:Gilead: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Holte:Amgen: Research Funding; Mundipharma: Research Funding.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".