| 1. |
- Kimby, Eva, et al.
(författare)
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Two courses of four weekly infusions of rituximab with or without interferon-α2a : final results from a randomized phase III study in symptomatic indolent B-cell lymphomas
- 2015
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 56:9, s. 2598-2607
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Tidskriftsartikel (refereegranskat)abstract
- Patients with advanced CD20 + indolent lymphoma, requiring therapy, were randomized to rituximab (four weekly infusions of 375 mg/m(2)) or to rituximab combined with 5 weeks of interferon-α2a (IFN-α2a) (3-4.5 MIU daily) as priming. Responding patients were eligible for a second cycle with the same allocated treatment. In total, 156 patients were randomized to rituximab and 157 to rituximab + IFN-α2a. In the intention-to treat (ITT) population, 244 patients (78%) responded to cycle 1. After a second cycle the complete remission/complete remission unconfirmed (CR/CRu) rate was 41% with the combination versus 24% with monotherapy (p = 0.005). The median time to treatment failure (primary endpoint) in ITT patients was 28 vs. 21.5 months, respectively (p = 0.302). After a long median follow-up (61 months), 33% (42% of patients responding to cycle 1) were still failure-free with an overall survival rate of 88% and with no difference between the treatment groups. The trial was registered at ClinicalTrials.gov Identifier: NCT01609010.
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| 2. |
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| 3. |
- Wahlin, Björn Engelbrekt, et al.
(författare)
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T Cells in Tumors and Blood Predict Outcome in Follicular Lymphoma Treated with Rituximab
- 2011
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 17:12, s. 4136-4144
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: T cells influence outcome in follicular lymphoma, but their contributions seem to be modified by therapy. Their impact in patients receiving rituximab without chemotherapy is unknown. EXPERIMENTAL DESIGN: Using flow cytometry, we evaluated the T cells in tumors and/or blood in a total of 250 follicular lymphoma patients included in two Nordic Lymphoma Group randomized trials that compared single rituximab with IFN-α2a-rituximab combinations. RESULTS: In univariate analysis, higher levels of CD3(+), CD4(+), and CD8(+) T cells in both tumors and blood correlated with superior treatment responses, and in multivariate analysis, tumor-CD3(+) (P = 0.011) and blood-CD4(+) (P = 0.029) cells were independent. CD4(+) cells were favorable regardless of treatment arm, but CD8(+) cells were favorable only in patients treated with single rituximab, because IFN-α2a improved responses especially in patients with low CD8(+) cell levels. Higher levels of blood-CD3(+) (P = 0.003) and blood-CD4(+) (P = 0.046) cells predicted longer overall survival, and higher levels of blood-CD8(+) cells longer times to next treatment (P = 0.046). CONCLUSIONS: We conclude that therapeutic effects of rituximab are augmented by tumor-associated T cells for rapid responses and by systemic T cells for sustained responses. CD4(+) and CD8(+) cells are both favorable in patients treated with rituximab. IFN-α2a abrogates the negative impact of few CD8(+) cells.
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| 4. |
- Enqvist, Monika, et al.
(författare)
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Systemic and Intra-Nodal Activation of NK Cells After Rituximab Monotherapy for Follicular Lymphoma.
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Monotherapy with the anti-CD20 monoclonal antibody rituximab can induce complete responses (CR) in patients with follicular lymphoma (FL). Resting FcRγIII+ (CD16+) natural killer (NK) cells respond strongly to rituximab-coated target cells in vitro. Yet, the contribution of NK cells in the therapeutic effect in vivo remains unknown. Here, we followed the NK cell repertoire dynamics in the lymph node and systemically during rituximab monotherapy in patients with FL. At baseline, NK cells in the tumor lymph node had a naïve phenotype albeit they were more differentiated than NK cells derived from control tonsils as determined by the frequency of CD56dim NK cells and the expression of killer cell immunoglobulin-like receptors (KIR), CD57 and CD16. Rituximab therapy induced a rapid drop in NK cell numbers coinciding with a relative increase in the frequency of Ki67+ NK cells both in the lymph node and peripheral blood. The Ki67+ NK cells had slightly increased expression of CD16, CD57 and higher levels of granzyme A and perforin. The in vivo activation of NK cells was paralleled by a temporary loss of in vitro functionality, primarily manifested as decreased IFNγ production in response to rituximab-coated targets. However, patients with pre-existing NKG2C+ adaptive NK cell subsets showed less Ki67 upregulation and were refractory to the loss of functionality. These data reveal variable imprints of rituximab monotherapy on the NK cell repertoire, which may depend on pre-existing repertoire diversity.
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| 5. |
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| 6. |
- Machaczka, Maciej, et al.
(författare)
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Association between P-glycoprotein and lymphoid antigen expression on myeloblasts versus therapy response and survival in de novo acute myeloid leukemia : long-term follow-up results
- 2012
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 29:3, s. 2070-2076
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Tidskriftsartikel (refereegranskat)abstract
- P-glycoprotein (PGP) over-expression on malignant cells is associated with poor prognosis and treatment outcome due to the development of a multidrug resistance phenotype. In this study, we analyzed the correlation between expression of PGP and lymphoid antigens (Ly) on leukemic myeloblasts versus response to therapy and survival in acute myeloid leukemia (AML). Fifty-one consecutive patients, aged 16–75 (median age 44.6 years), diagnosed with de novo AML between 1997 and 2000, and who received at least one induction chemotherapy course, were enrolled in the study. Expression of PGP on ≥10% of the myeloblasts (PGP+AML) at the time of diagnosis was observed in 21 patients (41%). The complete remission rate did not differ between PGP+ (13/21) and PGP− (20/30) patients (62 vs. 67%). Twelve of the 51 patients (24%) were still alive after a median follow-up time of 11.5 years (range 10.7–13.1). The Ly+AML patients showed significantly better overall survival compared with Ly−AML patients (8/18 vs. 4/33 patients alive at the last follow-up, P = 0.003). The subgroup of patients with co-expression of PGP and Ly also showed better overall survival compared with PGP+AML patients without Ly expression (4/8 vs. 0/13 patients alive at the last follow-up; P = 0.04). Our results suggest that expression of lymphoid antigens on PGP+ myeloblasts in AML can positively affect survival in AML patients, mainly due to a decreased relapse risk and better survival. Although the small number of patient may be perceived as a limitation of the study, the long follow-up period strengthens its value. Further prospective trials are needed to obtain more information concerning the association between PGP and lymphoid antigens in AML, which would put our results in their ultimate proper context.
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| 7. |
- Machaczka, Maciej, et al.
(författare)
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High incidence of chronic graft-versus-host disease after myeloablative allogeneic stem cell transplantation for chronic lymphocytic leukemia in Sweden : graft-versus-leukemia effect protects against relapse
- 2013
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1559-131X .- 1357-0560. ; 30:4, s. 762-762
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Tidskriftsartikel (refereegranskat)abstract
- Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment option for eligible patients with chronic lymphocytic leukemia (CLL). However, it is known that cure of CLL is only possible if a graft-versus-leukemia effect is present. Between 1994 and 2007, 48 adults underwent allo-SCT for poor-risk CLL in Sweden. Of these, ten (21%) patients aged 24-53 years (median: 46 years) received myeloablative conditioning (MAC), based on TBI and cyclophosphamide. All MAC patients had refractory, poorly controlled CLL before allo-SCT (partial remission in 9/10 patients and progressive disease in one). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II-IV was 30%. Nine patients developed chronic GVHD; extensive in four. Rates of nonrelapse mortality at 1, 3 and 10 years were 0, 10 and 20%, respectively. Two patients relapsed 36 and 53 months after transplantation. Six patients were still alive after a median follow-up time of 11.5 years (range 5.9-13.7). The probabilities of relapse-free and overall survival from 1, 3 and 5 years after transplantation were 100, 90 and 70%, and 100, 90 and 80%, respectively. Nevertheless, our analysis of long-term outcome after MAC allo-SCT for CLL suggests that younger patients with poorly controlled CLL may benefit from MAC allo-SCT.
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| 8. |
- Melén, Christopher M., et al.
(författare)
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Chemotherapeutic intensity and survival differences in young patients with diffuse large B-cell lymphoma : a Swedish Lymphoma Registry study
- 2016
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 175:4, s. 614-622
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Tidskriftsartikel (refereegranskat)abstract
- 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 60years 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=0002); the corresponding estimates were 40%, 55%, and 92% in aaIPI=3 (P=0014). There were large therapeutic differences between Sweden's six Healthcare Regions for aaIPI2: three were Moderate (more R-CHOP) and three Intensive (more R-CHOEP and R-HDA/M). Patients with aaIPI2 who were treated in the Intensive Regions, showed better OS (P<000005), particularly those with aaIPI=3 (5-year OS, 62% vs. 30%; P<000005). 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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| 9. |
- Wahlin, Björn Engelbrekt
(författare)
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Prognostic information from nonmalignant and malignant lymphocytes in follicular lymphoma in relation to therapy
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Follicular lymphoma is the most common indolent lymphoma. It is composed of centrocytes and centroblasts, residing in follicles that also harbour nonmalignant immune and stroma cells. Follicular lymphoma is graded according to the World Health Organization criteria that are based on the frequency of centroblasts. There is consensus that grades 1 and 2 are indolent, but not whether grade 3 is aggressive. Differences between grades 3A and 3B are also unclear. The nonmalignant cells in the microenvironment interact with the tumour cells and with each other. These interactions may be important for disease outcome. Since the introduction of the therapeutic monoclonal anti-CD20 antibody rituximab, the prognosis of follicular lymphoma has improved. It is likely that the mechanisms of rituximab affect and involve not only CD20+ follicular lymphoma cells but also the surrounding as well as the systemic immune cells. The aim of this thesis was to identify biological predictors for outcome in follicular lymphoma in relation to therapy. In paper I, using flow cytometry, we reported that higher numbers of CD8+ T cells in diagnostic lymph nodes are an independent predictor of better overall and disease-specific survival. This finding was reproduced in paper II in which computerised quantifications of tissue microarrays were used for a unifying multivariate model. This model showed that many cells in the microenvironment were independently important for outcome. Higher levels of cells positive for CD8 (cytotoxic T cells), forkhead box protein 3 (regulatory T cells) and programmed death-1 (PD-1+ T cells) correlated with good prognosis, but higher levels of cells positive for CD4 (helper T cells) and CD68 (macrophages) with poor. The best predictors for poor outcome were increasing CD4/CD8 and follicular/interfollicular CD4 ratios, suggesting that outcome is influenced by the balance between detrimental follicular B-helper and helper2 T-cells on one hand and favourable cytotoxic and helper1 T cells on the other. In paper III we used prospectively recorded flow cytometry analyses from two randomised trials where all patients received single rituximab with or without interferon-α priming. T cells in tumours (both CD4+ and CD8+) were associated with fast and good clinical responses to rituximab, while T cells in blood (both CD4+ and CD8+) correlated with slower but good and sustained responses, and were more important for survival. Interferon-α abrogated the dependence on high numbers of CD8+ cells (in both blood and tumours) for good rituximab responses. In paper IV we reviewed the follicular lymphoma grades in 828 patients with long follow-up times, of whom 40% received upfront rituximab. Compared with grade 1–3A patients and independently of clinical factors, grade 3B patients showed higher mortality but outcome was improved after upfront anthracyclines. Grade 3B patients experienced no relapses or deaths beyond five years of follow-up. Furthermore, patients with grade 3B were different in their clinical characteristics. In the entire population, patients with grade 3A had similar outcome as those with grade 1–2. However, in patients given upfront rituximab-containing therapy, increasing grades of 1, 2, and 3A correlated with better overall survival and time to treatment-failure, independently of clinical factors. We conclude that outcome in follicular lymphoma is determined by the balance between competing immune cells in the microenvironment and by their interactions with each other and with the tumour cells. Rituximab and interferon-α alter the prognostic properties of the immune cells, and also involve systemic T cells that may be very important for disease outcome. Grade 3B, or follicular large B-cell lymphoma, is a distinct, aggressive but curable entity. Grades 1, 2 and 3A are indolent and incurable. Increasing grades predict better outcome with rituximab therapy. Our findings suggest a future of personalised therapy based on biological characteristics of the patients and of the tumours.
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| 10. |
- Wahlin, Björn Engelbrekt, et al.
(författare)
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Real-world data on treatment concepts in classical Hodgkin lymphoma in Sweden 2000-2014, focusing on patients aged >60 years
- 2021
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Ingår i: eJHaem. - : John Wiley & Sons. - 2688-6146. ; 2:3, s. 400-412
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Tidskriftsartikel (refereegranskat)abstract
- Treatment for patients > 60 years with classical Hodgkin lymphoma (cHL) is problematic; there is no gold standard, and outcome is poor. Using the Swedish Lymphoma Registry, we analysed all Swedish patients diagnosed with cHL between 2000 and 2014 (N = 2345; median age 42 years; 691 patients were >60 years). The median follow-up time was 6.7 years. Treatment for elderly patients consisted mainly of ABVD or CHOP, and the younger patients were treated with ABVD or BEACOPP (with no survival difference). In multivariable analysis of patients > 60 years, ABVD correlated with better survival than CHOP (p = 0.027), and ABVD became more common over time among patients aged 61-70 years (p = 0.0206). Coinciding with the implementation of FDG-PET/CT, the fraction of advanced-stage disease increased in later calendar periods, also in the older patient group. Survival has improved in cHL patients > 60 years (p = 0.027), for whom ABVD seems superior to CHOP.
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