| 1. |
- Dahl, Mette, et al.
(författare)
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Expression patterns and prognostic potential of circular RNAs in mantle cell lymphoma : a study of younger patients from the MCL2 and MCL3 clinical trials
- 2022
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 36:1, s. 177-188
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is characterized by marked differences in outcome, emphasizing the need for strong prognostic biomarkers. Here, we explore expression patterns and prognostic relevance of circular RNAs (circRNAs), a group of endogenous non-coding RNA molecules, in MCL. We profiled the circRNA expression landscape using RNA-sequencing and explored the prognostic potential of 40 abundant circRNAs in samples from the Nordic MCL2 and MCL3 clinical trials, using NanoString nCounter Technology. We report a circRNA-based signature (circSCORE) developed in the training cohort MCL2 that is highly predictive of time to progression (TTP) and lymphoma-specific survival (LSS). The dismal outcome observed in the large proportion of patients assigned to the circSCORE high-risk group was confirmed in the independent validation cohort MCL3, both in terms of TTP (HR 3.0; P = 0.0004) and LSS (HR 3.6; P = 0.001). In Cox multiple regression analysis incorporating MIPI, Ki67 index, blastoid morphology and presence of TP53 mutations, circSCORE retained prognostic significance for TTP (HR 3.2; P = 0.01) and LSS (HR 4.6; P = 0.01). In conclusion, circRNAs are promising prognostic biomarkers in MCL and circSCORE improves identification of high-risk disease among younger patients treated with cytarabine-containing chemoimmunotherapy and autologous stem cell transplant.
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| 2. |
- Eskelund, Christian W., et al.
(författare)
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TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy
- 2017
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 130:17, s. 1903-1910
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Tidskriftsartikel (refereegranskat)abstract
- Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) andCDKN2A(20%),weresignificantly associatedwithinferioroutcomes(togetherwithMIPI, MIPI-c, blastoidmorphology, and Ki67 > 30%); however, inmultivariate analyses, only TP53 mutations (HR, 6.2; P <.0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P <.0001) andMIPI-c high-risk (HR, 2.6; P5.003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P <.0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.
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| 3. |
- Jerkeman, Mats, et al.
(författare)
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Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON) : a multicentre, open-label, single-arm, phase 2 trial
- 2018
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Ingår i: Tha Lancet Haematology. - : ELSEVIER SCI LTD. - 2352-3026. ; 5:3, s. E109-E116
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Tidskriftsartikel (refereegranskat)abstract
- Background Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone. Methods In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0-3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m(2)) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1-21. The primary endpoint was overall response assessed in the intention-totreat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials. gov, number NCT02460276. Findings Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17.8 months (IQR 14.7-20.9), 38 (76%, 95% CI 63-86) patients had an overall response, including 28 (56%, 42-69) patients who had a complete response and ten (20%, 11-33) who had a partial response. The most common grade 3-4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke. Interpretation Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial.
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| 4. |
- Olofsson, Sven-Erik, et al.
(författare)
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Population-Based Study of Treatment Guided by Tumor Marker Decline in Patients With Metastatic Nonseminomatous Germ Cell Tumor : A Report From the Swedish-Norwegian Testicular Cancer Group
- 2011
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 29:15, s. 2032-2039
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Tidskriftsartikel (refereegranskat)abstract
- Purpose From 1995 to 2003, 603 adult patients from Sweden and Norway with metastatic testicular nonseminomatous germ cell tumor (NSGCT) were included prospectively in a population-based protocol with strict guidelines for staging, treatment, and follow-up. Patients with extragonadal primary tumor or previous treatment for contralateral testicular tumor were excluded. The basic strategy was to individualize treatment according to initial tumor marker response. Methods Initial treatment for all patients was two courses of standard bleomycin, etoposide, and cisplatin (BEP), with tumor markers analyzed weekly. Good response was defined as a half-life (t(1/2)) for alpha-fetoprotein (AFP) of <= 7 days and/or for beta-human chorionic gonadotropin (beta-HCG) of <= 3 days. Patients with prolonged marker t(1/2) (ie, poor response) received intensification with addition of ifosfamide (BEP-if/PEI) in step 1. If poor response continued, the treatment was intensified with high-dose chemotherapy with stem-cell rescue as step 2. Results Overall, 99% of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median follow-up was 8.2 years. Seventy-seven percent of the patients were treated with BEP alone; 18% received intensification step 1%, and 5% received intensification step 2. Grouped according to International Germ Cell Consensus Classification, 10-year overall survival was 94.7% in good-prognosis patients, 90.0% in intermediate-prognosis patients, and 67.4% in poor-prognosis patients. Conclusion With detailed treatment protocols and a dedicated collaborative group of specialists, treatment results comparable to those reported from large single institutions can be achieved at national level. With the treatment principles used in Swedish-Norwegian Testicular Cancer Group study SWENOTECA IV, the survival of intermediate-prognosis patients is remarkable and close to that of good-prognosis patients.
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| 7. |
- Salim, Ruth, et al.
(författare)
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Exploring new prognostic biomarkers in Mantle Cell Lymphoma : a comparison of the circSCORE and the MCL35 score
- 2023
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Ingår i: Leukemia and Lymphoma. - 1042-8194. ; 64:8, s. 1414-1423
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is a biologically and clinically heterogeneous disease, emphasizing the need for prognostic biomarkers. In this study we aimed at comparing the prognostic value of two RNA-based risk scores, circSCORE and MCL35, in 149 patients from the MCL2 (ISRCTN87866680) and MCL3 (NCT00514475) patient cohorts. Both risk scores provided significant stratification of high versus low risk for progression free survival (PFS) and overall survival (OS). The circSCORE retained significant prognostic value in adjusted multivariable Cox regressions for PFS, but not for OS. Furthermore, circSCORE added significant prognostic value to MIPI in the pooled cohort (MCL2 and MCL3) for PFS and OS, and for PFS in MCL3 alone, outperforming Ki67 and MCL35. We suggest a new, combined MIPI-circSCORE with improved prognostic value, and with potential for future clinical implementation, if validated in a larger, independent cohort.
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