Mantle cell lymphomas (MCLs) represent a clinically aggressive lymphoma subtype with a poor prognosis. To explore a potential progress in outcome a historical comparison was performed using data from ...the Kiel Lymphoma Study Group (KLSG; 1975 to 1986) and the German Low Grade Lymphoma Study Group (GLSG; 1996 to 2004).
All patients with the histologically confirmed diagnosis of advanced-stage nonblastoid MCL were eligible. To minimize the potential heterogeneity of different risk profiles frequency matching was pursued. In addition, we adjusted for potential confounding variables by multiple Cox regression.
A total of 520 patients were assessable, 150 from KLSG and 370 from GLSG studies. The median overall survival was 2.7 years for KLSG patients as compared with 4.8 years for GLSG patients (P < .0001). The 5-year survival rates were 22% in the KLSG group (95% CI, 13% to 31%) as compared with 47% for GLSG treated patients (95% CI, 38% to 55%). The hazard ratio adjusted for performance status, lactate dehydrogenase, and age was 0.44 for GLSG patients (95% CI, 0.32 to 0.59).
Median overall survival of patients with advanced nonblastoid MCL almost doubled during the past 30 years. Potential reasons for this apparent improvement in overall survival include the application of anthracycline-containing regimens and new approaches, such as antilymphoma antibodies or stem cell transplantation. Advances in general supportive care, new diagnostic tools, and general improvement of life span might have also reinforced this effect. However, our results are questioning the validity of historical comparisons which had been frequently applied in previous trials.
Abstract The CD20 antigen characteristic for mature B-cell is also expressed on B-cell Non-Hodgkin lymphomas (NHL). It thus presents a possible target for immunotherapy. NHL respond readily to radio- ...and/or chemotherapy but this standard treatment bears a high risk of relapse. The specific monoclonal anti-CD20-antibody Rituximab, the first to be approved for clinical use, could be shown to improve response rates, response duration, and survival in NHL when combined with standard therapy. This review details the development, clinical application, and future perspectives of anti-CD20-antibody treatment of NHL, thereby proving the efficiency of immunotherapy via targeting of a tumor associated antigen.
Large field irradiation had been standard for early-stage follicular lymphoma (FL) for a long time. Although involved field radiotherapy (IF-RT) was recently favored because of the toxicity of large ...field irradiation, smaller irradiation fields have been accompanied with an increased risk of out-of-field recurrence. The MIR (MabThera
and Involved field Radiation) trial has shown that the combination of IF-RT at a dose of 30-40 Gy with the anti-CD20 antibody rituximab has led to similar efficacy compared with large field irradiation but with markedly reduced side effects. Immune modulating radiation therapy alone using low-dose radiotherapy (LDRT) of 2 × 2 Gy has been shown to be effective in FL. The GAZAI (GAZyvaro and response Adapted Involved-site Radiotherapy) trial aims to prove the efficacy of LDRT in combination with a novel anti-CD20 therapy.
The GAZAI trial is a non-randomized, open, non-controlled, German, multi-center phase II trial that includes patients with early-stage (I and II) nodular FL (grades 1 and 2) confirmed by central histological review. A maximum of 93 patients will be included in the trial. Patients will receive a combined approach of immunotherapy with the fully humanized anti-CD20 antibody obinutuzumab (Gazyvaro
) and involved site radiotherapy (IS-RT) with 2 × 2 Gy. The primary endpoint of the trial is the rate of metabolic complete response (CR), based on fludeoxyglucose positron emission tomography/computed tomography, after obinutuzumab and 2 × 2 Gy IS-RT in week 18. Secondary endpoints are morphologic CR rate in weeks 7 and 18 and month 6, progression-free survival, toxicity, recurrence patterns, overall survival, and quality of life. Additionally, minimal residual disease response is assessed. The risk for a potentially higher recurrence rate after LDRT will be minimized by additional salvage radiation up to the "full dose" of 40 Gy for patients who have less than a metabolic CR and morphologic partial response/CR, which will be evaluated in week 18, offering a response-adapted approach.
The goal of this trial is a further reduction of the radiation dose in patients with nodal early-stage FL showing a good response to a combination of LDRT and anti-CD20 immunotherapy and a comparison with the currently published MIR trial.
EudraCT number: 2016-002059-89. ClinicalTrials.gov identifier: NCT03341520 .
Recently, we have developed novel highly promising gene expression (GE) classifiers discriminating localized nodal (LFL) from systemic follicular lymphoma (SFL) with prognostic impact. However, few ...data are available in LFL especially concerning hotspot genetic alterations that are associated with the pathogenesis and prognosis of SFL. A total of 144 LFL and 527 SFL, enrolled in prospective clinical trials of the German Low Grade Lymphoma Study Group, were analyzed by fluorescence in situ hybridization to detect deletions in chromosomes 1p, 6q, and 17p as well as BCL2 translocations to determine their impact on clinical outcome of LFL patients. The frequency of chromosomal deletions in 1p and 17p was comparable between LFL and SFL, while 6q deletions and BCL2 translocations more frequently occurred in SFL. A higher proportion of 1p deletions was seen in BCL2‐translocation–positive LFL, compared with BCL2‐translocation–negative LFL. Deletions in chromosomes 1p, 6q, and 17p predicted clinical outcome of patients with SFL in the entire cohort, while only deletions in chromosome 1p retained its negative prognostic impact in R‐CHOP–treated SFL. In contrast, no deletions in one of the investigated genetic loci predicted clinical outcome in LFL. Likewise, the presence or absence of BCL2 translocations had no prognostic impact in LFL. Despite representing a genetic portfolio closely resembling SFL, LFL showed some differences in deletion frequencies. BCL2 translocation and 6q deletion frequency differs between LFL and SFL and might contribute to distinct genetic profiles in LFL and SFL.
Purpose: To evaluate the relationship between an estimated integral total body radiation dose delivered and phosphorylated histone H2AX protein (γ-H2AX) foci formation in peripheral blood lymphocytes ...of cancer patients.
Material and methods: γ-H2AX formation was quantified as the mean number of foci per lymphocyte (NmeanH2AX) and the percentage of lymphocytes with ≥n foci. The integrated total body radiation dose was estimated from the dose volume histogram of patient's body corrected for the proportion of the body scanned by computed tomography for 3D treatment planning.
Results: There was a strong linear correlation between the mean number of γ-H2AX foci per lymphocyte in the peripheral blood sample and integrated total body radiation dose (r = 0.83, p < 0.0001). The slope of the relationship was dependent on the site of body irradiated. In comparison to chest irradiation with a slope of 8.7 ± 0.8 foci Gy−1, the slopes for brain, upper leg and pelvic sites were significantly shallower by −4.7, −4.3, and −3.8 Gy−1, respectively (p < 0.0001), while the slope for upper abdomen irradiation was significantly larger by 9.1 ± 2.6 Gy−1 (p = 0.0007). There was a slight time effect since the start of radiotherapy on the slopes of the in vivo dose responses leading to shallower slopes (−1.5 ± 0.7 Gy−1, p = 0.03) later (≥10 day) during radiotherapy. After in vitro irradiation, lymphocytes showed 10.41 ± 0.12 foci per Gy with no evidence of inter-individual heterogeneity.
Conclusions: γ-H2AX measurements in peripheral lymphocytes after local radiotherapy allow the estimation of the applied integral body dose. The site and time dependence have to be considered.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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The MabThera and Involved field Radiotherapy study investigated efficacy and safety of involved field (IF) radiotherapy in combination with the ...anti‐CD20 antibody Rituximab for early‐stage follicular lymphoma (FL) in a prospective, single‐arm multicenter phase 2 design. Eighty‐five stage I–II FL patients received 8 cycles of Rituximab (375 mg/m2) and IF irradiation (30/40 Gy). The primary endpoint was progression‐free survival (PFS) 2 years from treatment start. Secondary endpoints were overall survival (OS), complete response rates, toxicity, quality of life, and minimal residual disease (MRD) response with protocol defined visits up to month 30. For the primary endpoint, PFS at 2 years was 85% for the intention‐to‐treat set. Long‐term data were captured in selected sites and evaluated as post hoc analysis in the per protocol (PP) set: PFS and OS were 78% and 96% at 5 years with a median follow‐up of 66 or 78 months, respectively. There were 17/76 recurrences in the PP set, of which 14 were outside the radiation volume only. MRD analyses revealed a clonal marker in 36% of patients at diagnosis. All but 1 marker positive patients experienced a molecular treatment response. There were 13 serious adverse events (4 related to the therapy) during the first 30 months. IF radiotherapy combined with Rituximab is well tolerated and highly efficient with low rates of recurrence in the first years in early‐stage FL. The efficacy is comparable with more aggressive therapy approaches without compromising the quality of life and maintains for an extended follow‐up of more than 5 years.
The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular ...features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ∼20% of newly diagnosed FL in which the detection rate of t(14;18) is only ∼50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an “advanced-stage signature” in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio HR, 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a “localized-stage signature” had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.
•Development of a robust GE signature discriminating localized-stage and advanced-stage FL.•The genetic signature may be responsible for the superior outcome of localized-stage FL.
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Knowledge on the pathogenesis of FL is mainly based on data derived from advanced/systemic stages of FL (sFL) and only small cohorts of localized FL (lFL) have been characterized intensively so far. ...Comprehensive analysis with profiling of somatic copy number alterations (SCNA) and whole exome sequencing (WES) was performed in 147 lFL and 122 sFL. Putative targets were analyzed for gene and protein expression. Overall, lFL and sFL, as well as BCL2 translocation-positive (BCL2+) and -negative (BCL2-) FL showed overlapping features in SCNA and mutational profiles. Significant differences between lFL and sFL, however, were detected for SCNA frequencies, e.g., in 18q-gains (14% lFL vs. 36% sFL; p = 0.0003). Although rare in lFL, gains in 18q21 were associated with inferior progression-free survival (PFS). The mutational landscape of lFL and sFL included typical genetic lesions. However, ARID1A mutations were significantly more often detected in sFL (29%) compared to lFL (6%, p = 0.0001). In BCL2 + FL mutations in KMT2D, BCL2, ABL2, IGLL5 and ARID1A were enriched, while STAT6 mutations more frequently occurred in BCL2- FL. Although the landscape of lFL and sFL showed overlapping features, molecular profiling revealed novel insights and identified gains in 18q21 as prognostic marker in lFL.
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