Aktuelle Standards in der Diagnostik und Therapie aggressiver B-Zell-Lymphome

2020 ◽  
Vol 145 (03) ◽  
pp. 151-154
Author(s):  
Birte Friedrichs ◽  
Norbert Schmitz ◽  
Georg Lenz
Keyword(s):  
Klinische Studien ◽  
Ältere Patienten ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Cell Of Origin ◽  
Junge Patienten ◽  
Diagnostik Und Therapie ◽  
Car T ◽  
Intrathekale Therapie ◽  
Who Klassifikation

Was ist neu? Molekulare Charakterisierung aggressiver Lymphome Die sogenannte „cell of origin“-Klassifikation von diffusen großzelligen B-Zell-Lymphomen (DLBCL) ist mittlerweile Bestandteil der revidierten WHO-Klassifikation von 2017. Dabei werden ABC- und GCB-DLBCL unterschieden. In der Praxis erfolgt diese Einteilung in der Regel unter Anwendung der Immunhistochemie, wobei meist der sogenannte Hans-Algorithmus eingesetzt wird. Erstlinientherapie von DLBCL-Patienten Die Hinzunahme verschiedener zielgerichteter Therapien konnte den Standard von 6–8 Zyklen R-CHOP-Chemoimmunotherapie bislang nicht verändern. Für junge Patienten bis 60 Jahre mit einem International Prognostic Index (IPI) von 0 kann die Therapie auf 4 Zyklen R-CHOP, gefolgt von 2 Applikationen Rituximab, reduziert werden. Prophylaxe von ZNS-Rezidiven bei DLBCL-Patienten Eine intrathekale Therapie mit chemotherapeutischen Substanzen hat keinen Einfluss auf die Verhinderung von Rezidiven im Bereich des zentralen Nervensystems (ZNS). Die Anwendung des ZNS-IPI zur Identifizierung von Patienten mit hohem Risiko für ein ZNS-Rezidiv erscheint sinnvoll, auch wenn es hierzu keine Daten aus randomisierten Studien gibt. Für Patienten mit einem hohen Risiko können 2 systemische Zyklen mit hochdosiertem Methotrexat zusätzlich zur Erstlinientherapie empfohlen werden. Behandlung von Patienten mit rezidiviertem oder therapierefraktärem DLBCL Patienten mit rezidiviertem und/oder refraktärem DLBCL erhalten eine Salvage-Chemotherapie, gefolgt von autologer oder allogener Stammzelltransplantation. Nach mindestens 2 Vortherapien sind aktuell 2 CAR-T-Zell-Produkte zugelassen. Dadurch erhalten auch ältere Patienten, die ggf. nicht für eine Transplantation infrage kommen, die Chance auf eine kurative Therapieoption. Ausblick Neue Substanzgruppen wie Antikörper-Medikamenten-Konjugate oder bispezifische Antikörper zeigen in Studien von Patienten mit rezidiviertem oder therapierefraktärem DLBCL sehr vielversprechende Ergebnisse. Aktuell laufende klinische Studien prüfen den Einsatz weiterer neuer Substanzen.

scholarly journals Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1350-1358 ◽  
Author(s):  
Ash A. Alizadeh ◽  
Andrew J. Gentles ◽  
Alvaro J. Alencar ◽  
Chih Long Liu ◽  
Holbrook E. Kohrt ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Single Gene ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractSeveral gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the “germinal center B cell–like” subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of “cell-of-origin” classification, “stromal signatures,” IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.

Cell of origin, germinal center versus nongerminal center, determined by immunohistochemistry on tissue microarray, does not correlate with outcome in patients with relapsed and refractory DLBCL

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3383-3385 ◽  
Author(s):  
Craig H. Moskowitz ◽  
Andrew D. Zelenetz ◽  
Tarun Kewalramani ◽  
Paul Hamlin ◽  
Simone Lessac-Chenen ◽  
...  
Keyword(s):  
De Novo ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Second Line ◽  
Cell Of Origin ◽  
Free Survival ◽  
Significant Difference ◽  
The Common

AbstractA number of prognostic factors affect outcome in patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL), including refractory disease and the second-line age-adjusted international prognostic index. In de novo DLBCL, the cell of orgin, as determined by expression microarray analysis or immunohistochemistry (IHC), predicts event-free survival (EFS). We evaluated the cell of origin, as well as other pathologic markers of outcome, on the repeat biopsy specimen of 88 transplantation-eligible patients undergoing ifosfamide, carboplatin, etoposide (ICE) second-line chemotherapy (SLT) followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to see if were they prognostic in the salvage setting. Pretreatment clinical factors were well balanced between the cohorts. There was no significant difference in response to SLT, HDT, event-free or overall survival based on the cell of origin or any of the common pathologic markers examined. The cell of origin as determined by IHC does not predict outcome in transplantation-eligible patients with relapsed or primary refractory DLBCL.

scholarly journals Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL

Blood ◽  
2019 ◽  
Vol 133 (9) ◽  
pp. 919-926 ◽  
Author(s):  
Magdalena Klanova ◽  
Laurie H. Sehn ◽  
Isabelle Bence-Bruckler ◽  
Federica Cavallo ◽  
Jie Jin ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Cns Relapse ◽  
Relapse Prediction ◽  
Expression Status ◽  
Dual Expression

Abstract Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS–International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; P = .02) and activated B-cell‒like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; P = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; P = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #NCT01287741.

L-mind: MOR208 combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large b-cell lymphoma (R-R DLBCL)—A single-arm phase II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7514-7514 ◽  
Author(s):  
Kami J. Maddocks ◽  
Eva González Barca ◽  
Wojciech Jurczak ◽  
Anna Marina Liberati ◽  
Johannes Duell ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
International Prognostic Index ◽  
Single Agent ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Cell Of Origin

7514 Background: The Fc-enhanced CD19 antibody MOR208 and the immunomodulatory drug LEN have demonstrated single agent activity in patients (pts) with R-R DLBCL. MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing phase II study assesses the safety and efficacy of MOR208 + LEN in pts with R-R DLBCL. Methods: Pts >18 years old with R-R DLBCL, ECOG 0–2, adequate organ function, having previously received ≥1 but not more than 3 prior therapies, including ≥1 CD20-targeting regimen and who are not candidates for autologous stem cell transplant (ASCT), are eligible. Treatment comprises up to 12, 28-day (d) cycles (C) of MOR208 12 mg/kg IV, weekly during C1–3 (loading dose d4 of C1); every second week C4–12 + LEN 25 mg po d1–21, C1–12. Pts progression-free after 12 cycles receive up to 12 additional cycles of MOR208 (every second week). The primary endpoint is the overall response rate (ORR) by central radiology assessment. Secondary endpoints include disease control, duration of response, progression-free and overall survival, safety, and response by cell of origin and other biomarkers. A preplanned safety evaluation was undertaken. Results: 31 of 80 planned pts were enrolled prior to data cutoff (3 January 2017). Median age was 74 years (range 47–82); 45% of pts received ≥2 prior lines of therapy; 23% had rituximab refractory disease; 74% had Ann Arbor stage ≥III disease; 65% had elevated lactate dehydrogenase level, and 52% had a poor revised International Prognostic Index (3-5). The most common treatment-emergent adverse events (any grade/grade ≥3 [% pts]) were neutropenia (39/26), anemia (23/0) thrombocytopenia (16/6), infections (26/10) diarrhea (13/0), pyrexia (13/0), and rashes (13/6). Of 26 response evaluable pts (median follow-up 3.3 months), ORR (investigator assessed) was 58% (15 pts), with 7 (27%) complete responses. Median time to response was 1.8 months. Conclusions: The combination of MOR208 + LEN is well tolerated and shows promising activity in pts with R-R DLBCL. Accrual and follow-up of pts is ongoing, as are cell of origin and other biomarker analyses. Clinical trial information: NCT02399085.

scholarly journals End-of-treatment PET/CT predicts PFS and OS in DLBCL after first-line treatment: results from GOYA

2021 ◽  
Vol 5 (5) ◽  
pp. 1283-1290
Author(s):  
Lale Kostakoglu ◽  
Maurizio Martelli ◽  
Laurie H. Sehn ◽  
David Belada ◽  
Angelo-Michele Carella ◽  
...  
Keyword(s):  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Published Data ◽  
Cell Of Origin ◽  
Term Survival ◽  
Entire Cohort ◽  
End Of Treatment

AbstractGOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)–based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose–PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee–assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.

Tissue Microarray in DLBCL Patients receiving R-CHOP Chemo-Immunotherapy Shows Survival Benefit for Coexpression of LMO2/BCL6

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1585-1585 ◽  
Author(s):  
Colm Keane ◽  
Linda Shen ◽  
Erica Han ◽  
Jamie P Nourse ◽  
Rod Lea ◽  
...  
Keyword(s):  
Overall Survival ◽  
Univariate Analysis ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Germinal Centre ◽  
Cell Of Origin ◽  
Event Free Survival ◽  
Free Survival ◽  
Dual Positivity ◽  
Improved Outcome

Abstract Abstract 1585 Background: Diffuse Large B-cell Lymphoma (DLBCL) is a heterogeneous disease with variable outcome within international prognostic index (IPI) categories. Previous studies indicate expression of germinal centre B-cell (GCB) markers predict good outcome and that non-GCB sub-types may benefit from alternate therapies. A variety of immunohistochemical combinations have been proposed. However results are inconsistent and there is limited data comparing strategies. The need for a robust, practical method to distinguish GCB-DLBCL remains. We evaluated co-expression of the GCB proteins LMO2 and BCL6 with the Choi, Hans and Tally algorithms in patients treated with R-CHOP chemo-immunotherapy. Patients and Methods: Seventy-five DLBCL patients, chosen solely on availability of material for tissue microarray, were studied using immunohistochemistry for FOXP1, MUM1, CD10, BCL6, LMO2 and GCET1 on original biopsies. Clinical data was obtained from a prospectively maintained database. Results were correlated with event free (EFS) and overall survival (OS). Results: The cohort was typical for DLBCL described in the literature with 63% of patients aged over 60. The International Prognostic Index (IPI) predicted overall survival (p<0.001) with 36% of patients with a low IPI score (0,1), 41% with intermediate score (2,3) and 23% with a high IPI score (4,5). The three year event free and overall survival (EFS and OS) were 68% and 73% respectively with a median follow up of 37 months. None of the cell of origin algorithm predicted for EFS or OS. The Hans (49%) and Choi algorithms (43%) typed similar number of patients as GCB but the Tally method (26%) typed patients less frequently as GCB. This difference was statistically different (p=0.014). No single marker predicted for outcome, however there was a trend for patients who were BCL6 positive to have improved outcome (p=0.06). 53% of patients were positive for BCL6. BCL6 was a significant predictor of improved event free survival on univariate analysis (p=0.016). Interestingly, patients who were positive for both LMO2 and BCL6 (26% of total) had a significantly improved outcome on univariate analysis for both event free (p=0.01) and overall survival (p=0.0036). LM02/BCL6 dual positivity retained significance for event free survival independent of IPI on multivariate analysis (p=0.017). It was not possible to demonstrate independence from IPI for overall survival using Cox regression as none of the nineteen dual positive patients have died. There was no significant differences between patients who were LMO2/BCL6 positive and the rest of the cohort with respect to any of the IPI factors. Of note, LMO2 on its own was independent of IPI with regards to overall survival despite not reaching significance at the univariate level (p=0.049). In the subgroup of patients who were positive for BCL6 approximately half were also positive for LMO2. There was a significant difference in overall survival between these BCL6 single positive and BCL6/LMO2 dual positive tumours (p=0.003) with improved outcome seen in the dual positive patients. Similarly those LMO2 positive patients who were BCL6 negative had very poor outcome compared to LMO2/BCL6 dual positive tumours (p=0.0002). Dual positivity for BCL6/LMO2 was strongly associated with germinal centre phenotype with eighty per cent of these patients typing for this cell of origin (p=0.0004). Germinal centre DLBCL as typed by the Choi algorithm could be separated into two significantly different groups with different overall survival based on LMO2/BCL6 dual positivity (p=0.01) Conclusion: LMO2/BCL6 dual positivity is a prognostic marker in DLBCL treated with R-CHOP that is independent of IPI, and predicts outcome in GCB typed tumours. Should these findings be prospectively validated, the strategy would be easily transferable to the diagnostic laboratory. Disclosures: No relevant conflicts of interest to declare.

Psychotherapie von Patienten mit Depression und Abhängigkeitserkrankung

2011 ◽  
Vol 57 (5) ◽  
pp. 373-381
Author(s):  
Sabine Loeber ◽  
Christina Dinter ◽  
Karl Mann
Keyword(s):  
Klinische Studien ◽  
Depressive Störungen ◽  
Depressive Symptome ◽  
Diagnostik Und Therapie

Fragestellung: Im Verlauf einer Suchterkrankung kommt es häufig zum Auftreten depressiver Störungen. Depressive Symptome, die auch nach Abschluss der Entzugsphase persistieren, erweisen sich als ein zentraler Prädiktor für einen Rückfall und sollten im Rahmen von Diagnostik und Therapie berücksichtigt werden. Methodik: In der vorliegenden Arbeit wurde eine systematische Literaturrecherche durchgeführt, um sowohl randomisierte Therapievergleichsstudien als auch weitere klinische Studien zu identifizieren, die die Effektivität einer integrativen Behandlung von Abhängigkeitserkrankungen und Depression untersuchen. Ergebnisse: Die Ergebnisse der wenigen identifizierten Untersuchungen zeigen, dass durch ein integratives Behandlungskonzept, bei dem sowohl die Suchterkrankung als auch depressive Störungen behandelt werden, eine Reduktion depressiver Symptome und eine Steigerung der Abstinenzquote erzielt wird. Schlussfolgerungen: Methodische Mängel der vorliegenden Untersuchungen bzw. die noch ausstehende Replikation von Befunden schränken jedoch gegenwärtig die vorliegenden positiven Ergebnisse zur integrierten Behandlung ein. Ferner gestaltet sich die Etablierung integrierter Behandlungsansätze aufgrund der nach wie vor zu beobachtenden Trennung zwischen Einrichtungen der Suchtkrankenhilfe und allgemein-psychiatrischen Einrichtungen schwierig.

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