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- Jerkeman, Mats, et al.
(författare)
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MRD-driven treatment with venetoclax-R2 in mantle cell lymphoma : the Nordic Lymphoma Group MCL7 VALERIA trial
- 2024
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 8:2, s. 407-415
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Tidskriftsartikel (refereegranskat)abstract
- Despite improvements in treatment of mantle cell lymphoma (MCL), most patients eventually relapse. In this multicenter phase 1b/2 trial, we evaluated safety and efficacy of minimal residual disease (MRD)-driven venetoclax, lenalidomide, and rituximab (venetoclax-R2) in relapsed/refractory (R/R) MCL and explored the feasibility of stopping treatment in molecular remission. The primary end point was overall response rate (ORR) at 6 months. After dose escalation, the recommended phase 2 dose was lenalidomide 20 mg daily, days 1 to 21; venetoclax 600 mg daily after ramp-up; and rituximab 375 mg/m(2) weekly for 4 weeks, then every 8 weeks. MRD monitoring by RQ-PCR was performed every 3 months. When MRD-negativity in the blood was reached, treatment was continued for another 3 months; if MRD-negativity was then confirmed, treatment was stopped. In total, 59 patients were enrolled, with a median age of 73 years. At 6 months, the ORR was 63% (29 complete remission [CR], 8 partial remission [PR]), and 40% (4 CR, 2 PR) for patients previously failing a Bruton tyrosine kinase (BTK) inhibitor. Median progression-free survival (PFS) was 21 months, with median overall survival of 31 months. TP53 mutation was associated with inferior PFS (P < .01). Overall, 28 patients (48%) discontinued treatment in molecular remission, and 25 remain MRD negative after a median of 17.4 months. Hematological toxicity was frequent, with 52 of 59 (88%) patients with G3-4 neutropenia and 21 of 59 (36%) patients with G3-4 thrombocytopenia. To conclude, MRD-driven venetoclax-R2 is feasible and tolerable and shows efficacy in R/R MCL, also after BTK inhibitor failure.
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- Mylam, Karen Juul, et al.
(författare)
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F-18-fluorodeoxyglucose-positron emission tomography/computed tomography after one cycle of chemotherapy in patients with diffuse large B-cell lymphoma: results of a Nordic/US intergroup study
- 2015
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Ingår i: Leukemia & Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 56:7, s. 2005-2012
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the predictive value of interim positon emission tomography (I-PET) after one course of chemoimmunotherapy in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). One hundred and twelve patients with DLBCL were enrolled. All patients had PET/computed tomography (CT) scans performed after one course of chemotherapy (PET-1). I-PET scans were categorized according to International Harmonization Project criteria (IHP), Deauville 5-point scale (D 5PS) with scores 1-3 considered negative (D 5PS>3) and D 5PS with scores 1-4 considered negative (D 5PS = 5). Ratios of tumor maximum standardized uptake value (SUVmax) to liver SUVmax were also analyzed. We found no difference in progression-free survival (PFS) between PET-negative and PET-positive patients according to IHP and D 5PS>3. The 2-year PFS using D 5PS = 5 was 50.9% in the PET-positive group and 84.8% in the PET-negative group (p = 0.002). A tumor/liver SUVmax cut-off of 3.1 to distinguish D 5PS scores of 4 and 5 provided the best prognostic value. PET after one course of chemotherapy was not able to safely discriminate PET-positive and PET-negative patients in different prognostic groups.
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- Nyman, Heidi, et al.
(författare)
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Bcl-2 but not FOXP1, is an adverse risk factor in immunochemotherapy-treated non-germinal center diffuse large B-cell lymphomas
- 2009
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 82:5, s. 364-372
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Tidskriftsartikel (refereegranskat)abstract
- Non-germinal center (non-GC) phenotype, high level expression of the transcription factor forkhead box protein P1 (FOXP1) and anti-apoptotic protein Bcl-2 have been identified as unfavorable prognostic factors for diffuse large B-cell lymphoma (DLBCL) patients treated with chemotherapy. Our aim was to re-evaluate the prognostic impact of these biologic factors on the survival of the patients treated with immunochemotherapy. Expression of Bcl-2 and FOXP1, and cell of origin based on the Hans algorithm were determined immunohistochemically from samples of 117 de novo DLBCL patients treated with R-CHOP and R-CHOEP regimens, and correlated with clinical data. Consistent with our previous studies, no significant difference in 2-yr survival rates between the GC- and non-GC phenotypes was found. Both FOXP1 and Bcl-2 expression were associated with the non-GC phenotype. For all patients, no prognostic impact of FOXP1 positivity on survival was observed. However, Bcl-2 negative patients had a better survival as compared to Bcl-2 positive patients [failure free survival (FFS) 97% vs. 71%, P = 0.001 and overall survival (OS) 97% vs. 82%, P = 0.034]. When Bcl-2 related survival was analyzed in the GC- and non-GC subgroups, a significant prognostic effect of Bcl-2 on FFS was seen only in the non-GC group of patients (positive 65% vs. negative 100%, P = 0.011). A trend for the difference in OS was also observed (positive 84% vs. negative 100%, P = 0.082). The data demonstrate that expression of Bcl-2 and FOXP1 is associated with the non-GC phenotype, but only Bcl-2 expression continues to be of prognostic significance in DLBCL patients treated with immunochemotherapy.
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- Nyman, Heidi, et al.
(författare)
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Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP
- 2009
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 22:8, s. 1094-1101
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression profiling studies initially enabled diffuse large B-cell lymphoma to be divided into germinal center and activated B-cell-like subtypes, which define high-and low-risk patient groups when treated with chemotherapy. Attempts to reproduce the prognostic classification immunohistochemically have, however, provided inconsistent results. The aim of this study was to determine whether modified immunohistochemical classification of cell of origin focusing on activated B-cell-like markers could be used to predict the outcome of immunochemotherapy-treated diffuse large B-cell lymphoma patients. The expression of CD10, Bcl-6, MUM1/IRF4, Bcl-2, and FOXP1 was determined immunohistochemically from 88 samples of diffuse large B-cell lymphoma patients treated uniformly with R-CHOP. When the modified classification using MUM1/IRF4 and FOXP1 positivities as activated B-cell-like markers was applied to distinguish the patients between the activated B-cell-like and other diffuse large B-cell lymphoma subtypes, a significantly worse outcome was seen for the patients with the activated B-cell-like phenotype (3-year failure-free survival 63 vs 82%, P = 0.048, overall survival 69 vs 85%, P = 0.110). Similarly, according to the Muris algorithm, the group 2 patients representing Bcl-2-positive post-germinal center patients showed an inferior outcome in comparison to the group 1 patients (failure-free survival 59 vs 81%, P = 0.041, overall survival 67 vs 82%, P = 0.159). In contrast, when the classification of the same cohort was performed according to the Hans algorithm, no significant difference in survival was observed between the germinal center and non-germinal center patients. In conclusion, the data suggest that both the modified activated B-cell-like and Muris classifications define the non-germinal center phenotype as an adverse risk factor in R-CHOP-treated diffuse large B-cell lymphoma patients. Modern Pathology (2009) 22, 1094-1101; doi: 10.1038/modpathol.2009.73; published online 15 May 2009
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- Pulczynski, Elisa Jacobsen, et al.
(författare)
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Age-adjusted combined immunochemotherapy without radiotherapy in newly diagnosed PCNSL : A phase II trial of the Nordic Lymphoma Group
- 2011
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Ingår i: 53rd ASH Anual Meeting and Exposition. ; , s. 696-696
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Konferensbidrag (refereegranskat)abstract
- Patients and Methods: From May 2007 to October 2010, 66 newly diagnosed primary central nervous system lymphoma (PCNSL) patients (M/F ratio 1:1) were enrolled. Younger patients (≤65 yrs; N=39) received 6 three-weekly cycles of chemotherapy consisting of: high-dose (HD)-methotrexate (MTX) (cycles 1, 2, 4 and 5), HD-cytosine arabinoside (AraC) (cycles 3 and 6) in addition to Rituximab (cycle 1 only), ifosfamide (cycles 1 and 4), cyclophosphamide (cycles 2 and 5), vincristine (cycles 2 and 5), vindesine (cycles 3 and 6), and dexamethasone (all 6 cycles). Depocyte® was delivered intratechally during the HD-MTX cycles. Elderly patients (66-75 yrs; N=27) received an identical Rituximab-containing 1st cycle. Cyclophosphamide and ifosfamide were replaced by temozolamide (cycles 2 to 6), which was also given as maintenance in patients with chemosensitive disease, and vincristine was omitted. No radiotherapy was given. Response was determined after the 2nd, 4th and 6thchemotherapy cycle by cerebral MRI and assessed according to International Primary CNS Lymphoma Coordinating Group criteria. The primary endpoint was overall survival (OS), secondary endpoints were progression-free survival (PFS), overall response rate (ORR), systemic toxicity and neurotoxicity assessed as Mini Mental State Examination (MMSE) and Functional Independence Measure (FIM). Results: The median age was 64 yrs overall, 55 yrs (range 40-65) for younger and 70 yrs (range 66-75 years) for elderly patients. In 56 patients, the International Extranodal Lymphoma Study Group prognostic score was: 0-1 (N=5), 2-3 (N=36) and 4-5 (N=15). In the remaining 10 patients, lumbar puncture was not performed in five and spinal fluid protein concentration not reported in additional five cases. Response assessment after completion of induction treatment was performed in 43 out of 66 patients and showed complete remission (CR/CRu) in 30 patients, partial remission (PR) in 5 and progressive disease (PD) in 8. The ORR was 53 %. In 23 patients, response could not be evaluated due to early progression (n=8), toxic death (n=4), poor performance (n=3), neurotoxicity (n=5), or other causes (n=3). Of the 27 elderly patients, 15 continued to maintenance therapy. Of these, 14 have completed the maintenance schedule. Remission status at month 3 was CR in 13 and PD in 1 patient. With a median follow-up of 11.1 months (range 0.6-40.2) the 3-yr OS was 54.6% with no significant difference between younger and elderly patients (56.4% vs 51.9% respectively, p=0.32). The 3-yr PFS was 35.1% (32.9% in younger and 38.2 % in elderly patients; p=0.96). There were four septic deaths. Grade 3-4 hematological toxicity was seen in 79 % of the patients. Arachnoditis-like symptoms occurred in 13 patients. In all but two patients, the symptoms resolved within less than a week. MMSE and FIM were recorded both before and after therapy in 32 patients. Scores improved in 18 and 20 patients, respectively. Conclusion: In conclusion, the schedule applied in the present study led to a 3 yr PFS of 35%. Surprisingly, no significant outcome difference was found between the younger and the elderly patients. The majority of treatment failures were due to early progressive disease under induction therapy. Although the follow-up of our study is short, de-escalation of induction treatment intensity by introduction of a less toxic agent as temozolomide, and its subsequent use in a maintenance schedule may explain a possible survival benefit of this strategy in elderly patients. Disclosures: No relevant conflicts of interest to declare.
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- Riihijarvi, Sari, et al.
(författare)
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High serum vascular endothelial growth factor level is an adverse prognostic factor for high-risk diffuse large B-cell lymphoma patients treated with dose-dense chemoimmunotherapy
- 2012
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 89:5, s. 395-402
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To determine whether serum vascular endothelial growth factor (s-VEGF) levels and VEGF gene expression in tumor tissue predict survival of diffuse large B-cell lymphoma (DLBCL) patients treated with chemoimmunotherapy. Methods VEGF levels were measured in serum samples from 102 patients <65yrs with high-risk DLBCL using a quantitative sandwich enzyme immunoassay technique. Exon array data set of tumor tissues from 32 patients was concurrently used to determine VEGF-A exon and gene expression. All patients were treated in a Nordic phase II study with six dose-dense chemoimmunotherapy courses followed by systemic central nervous system prophylaxis. Results After a median follow-up time of 40months, 3-yr progression-free survival (PFS) was inferior in patients with high s-VEGF levels compared to those with low levels (59% vs. 83%, P=0.005). The relative risk of progression or relapse was 3.1-fold (95% confidence interval 1.346.91, P=0.008). The predictive capacity of s-VEGF levels on PFS was most pronounced in the DLBCLs of non-germinal center subtype. In contrast to serum data, VEGF mRNA expression in the lymphoma tissue did not predict outcome, and no correlation was found between s-VEGF levels and lymphoma VEGF expression. Conclusion Pretreatment s-VEGF level is a predictor of PFS after chemoimmunotherapy and may help to further stratify high-risk DLBCL patients into low- and high-risk groups.
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| 11. |
- Riihijarvi, Sari, et al.
(författare)
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Male gender is an adverse prognostic factor in B-cell lymphoma patients treated with immunochemotherapy
- 2011
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 86:2, s. 124-128
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Tidskriftsartikel (refereegranskat)abstract
- Male gender is an adverse prognostic factor in Hodgkin's lymphoma, but no such association has yet been established in non-Hodgkin lymphomas. Here, we have evaluated whether gender has prognostic impact on the survival of patients with B-cell non-Hodgkin lymphoma in the postrituximab era of lymphoma therapies. The study populations consisted of 217 diffuse large B-cell lymphoma (DLBCL) and 110 follicular lymphoma (FL) patients treated with immunochemotherapy. Hundred and sixty chemotherapy-treated DLBCL patients served as a control group. According to Kaplan-Meier analyses, female patients had a significantly better progression-free survival than men both in DLBCL (4 yr PFS 75% vs. 60%; P = 0.013) and in FL (4 yr PFS 68% vs. 52%, P = 0.036) patients treated with immunochemotherapy. In chemotherapy-treated DLBCL patients, no difference in survival between the genders was found. The results support the idea that women seem to respond better to rituximab.
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| 12. |
- Riihijarvi, Sari, et al.
(författare)
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Prognostic impact of protein kinase C beta II expression in R-CHOP-treated diffuse large B-cell lymphoma patients
- 2010
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 23:5, s. 686-693
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Tidskriftsartikel (refereegranskat)abstract
- Development of targeted agents for the treatment of diffuse large B-cell lymphoma includes clinical evaluation of enzastaurin, an agent that suppresses signaling through protein kinase C-beta and AKT pathways. To determine whether protein kinase C-beta expression has prognostic significance for diffuse large B-cell lymphoma patients treated with immunochemotherapy, we analyzed the expression of protein kinase C-beta II, BCL-2 and cell of origin immunohistochemically from pretreatment samples of 95 diffuse large B-cell lymphoma patients. All patients received rituximab with CHOP or CHOEP. According to Kaplan-Meier analyses, overall survival at 3 years was better among the patients with low than high protein kinase C-beta II protein levels (94 vs 76%, P = 0.036). The prognostic value of protein kinase C-beta II expression on survival was seen in the patients with low and high International Prognostic Index risk groups, and in all molecular entities. Gene expression data from an independent set of 233 diffuse large B-cell lymphoma patients treated with a combination of rituximab and CHOP-like chemotherapy was analyzed in comparison. Accordingly, a better 3-year overall survival was observed among the subgroup with low protein kinase C-beta II mRNA levels (84 vs 68%, P = 0.005). In multivariate analysis with cell of origin, protein kinase C-beta II mRNA expression remained as an independent predictor for overall survival. Together, the data show that protein kinase C-beta II expression has prognostic significance in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Modern Pathology (2010) 23, 686-693; doi: 10.1038/modpathol.2010.43; published online 26 February 2010
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