The Prognostic Impact Of Gene Rearrangements and Protein Expression Of MYC, BCL2 and BCL6 In Young High-Risk Patients With DLBCL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4262-4262 ◽  
Author(s):  
Heike Horn ◽  
Marita Ziepert ◽  
Thomas F.E. Barth ◽  
Heinz-Wolfram Bernd ◽  
Martin Wartenberg ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Protein Expression ◽  
In Situ Hybridisation ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Prognostic Impact ◽  
Fluorescence In Situ Hybridisation ◽  
High Risk Patients ◽  
Risk Patients

Abstract Purpose A number of retrospective analyses have looked into the prognostic implication of MYC, BCL2 and BCL6 rearrangements and protein expression for MYC, BCL2 and BCL6 in patients with diffuse large B-cell lymphoma (DLBCL). Many of these studies suffer from small patient cohorts and differing or unknown treatment strategies (with or without Rituximab) administered to patients under study. Furthermore, the median age of these patients was relatively high. We for the first time report on the prognostic consequences of MYC, BCL2 and BCL6 alterations in younger (18-60 years) high-risk patients (aaIPI 2 or 3) with DLBCL. Patients and Methods The MegaCHOEP study (Schmitz et al. Lancet Oncology 2012: 13, 1250) randomized patients to 8xCHOEP-14 or sequential high-dose therapy supported by repeated infusions of autologous stem cells. Both treatment arms included 6 infusions of R (375 mg/ sqm). The median patient age was 48 years, and 27% of patients scored an aaIPI of 3. Paraffin-embedded tumor samples from 112 de novo DLBCL were investigated using immunohistochemistry for MYC, BCL2, and BCL6, and fluorescence in-situ hybridisation (FISH) to detect breaks of MYC, BCL2 and BCL6. Results Rearrangements of MYC, BCL2 and BCL6 were detected in 13.6%, 20.7% and 30.9% of DLBCL, respectively. A double or triple hit constellation occurred in 10.8%. Presence of BCL2 breaks (RR=4.7, 95% CI: 1.8-12.2) and MYC breaks (RR=2.4, 95% CI: 0.8-7.5), but not of BCL6 breaks were associated with inferior overall survival in univariate and multivariate analyses adjusted for aaIPI and treatment arm. Protein overexpression of MYC ≥30% (RR=2.4, 95% CI: 0.9-6.5), but not BCL2 (≥60%) or BCL6 (≥30%) indicated inferior overall survival. BCL2 overexpression was associated with inferior EFS (RR=2.2, 95% CI: 0.9-5.5) and PFS (RR=2.8, 95% CI: 1.0-8.2). If the same cutpoint for BCL2 used for a similar analysis in elderly patients treated on the RICOVER-60 trial (Horn et al. Blood 2013) was applied, no differences in EFS or PFS were observed. Conclusion Rearrangements of MYC and BCL2 seem to be relevant prognostic factors also in young high-risk patients. The frequencies of MYC and BCL2 rearrangements are not substantially higher than reported for other, mostly elderly patient groups carrying IPI scores from 0 - 5; it seems unlikely, therefore, that the rearrangements described here (completely) explain the poor prognosis of young, high-risk patients. The prognostic role of BCL2, BCL6, and MYC as well as other biological risk factors must be validated in independent data sets. Disclosures: No relevant conflicts of interest to declare.

The prognostic significance of early molecular and cytogenetic response for long-term progression-free and overall survival in imatinib-treated chronic myeloid leukemia (CML).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6510-6510
Author(s):  
Rudiger Hehlmann ◽  
Benjamin Hanfstein ◽  
Martin C Müller ◽  
Philipp Erben ◽  
Michael Lauseker ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Prognostic Impact ◽  
High Risk Patients ◽  
Risk Patients

6510 Background: In the face of competing first line treatment options for CML early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of an alternative therapy. We sought to evaluate the prognostic impact of early response landmarks. Methods: A total of 1,303 newly diagnosed imatinib-treated patients (pts) from the randomized CML Study IV were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). Median follow-up was 4.7 years (range 0-9). The BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (BCR-ABLIS). The proportion of Philadelphia-chromosome positive metaphases (Ph+) was determined by conventional metaphase analysis. To confirm the prognostic significance of early molecular response, an independent validation sample of 174 pts treated with imatinib within the IRIS trial was analyzed. Results: The persistence of >10% BCR-ABLIS at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with 1-10% BCR-ABLIS (41% of pts; 5-year OS: 94%; p=0.012), and from a group with <1% BCR-ABLIS (31% of pts; 5-year OS: 97%; p=0.004). By cytogenetics high-risk patients could be identified by the persistence of >35% Ph+ (27% of pts; 5-year OS: 87%) as compared to ≤35% Ph+ (73% of pts; 5-year OS: 95%; p=0.036). At 6 months the >1% BCR-ABLIS group (37% of pts; 5-year OS: 89%) showed inferior survival compared to ≤1% (63% of pts; 5-year OS: 97%; p<0.001); survival of the >0% Ph+ group (34% of pts; 5-year OS: 91%) was inferior to 0% Ph+ (66% of pts; 5-year OS: 97%; p=0.015). Regarding the IRIS pts 3 month BCR-ABLIS >10% (25% of pts; 8-year OS: 81%) was associated with inferior survival compared to ≤10% (75% of pts; 8-year OS: 93%; p=0.011). Conclusions: Failure to achieve the response landmarks of 10% BCR-ABLIS or 35% Ph+ at 3 months of imatinib treatment and 1% BCR-ABLIS or 0% Ph+ at 6 months identifies high-risk patients which might benefit from an early change of therapy.

Is high-dose nafamostat mesilate effective for the prevention of post-ERCP pancreatitis, especially in high-risk patients?

Pancreatology ◽  
2013 ◽  
Vol 13 (2) ◽  
pp. e42
Author(s):  
D.H. Kang ◽  
C.W. Choi ◽  
S.B. Park ◽  
H.W. Kim ◽  
J.H. Park ◽  
...  
Keyword(s):  
High Risk ◽  
High Dose ◽  
Nafamostat Mesilate ◽  
High Risk Patients ◽  
Risk Patients

scholarly journals Open-Labeled, Multicenter Phase II Study of Bortezomib for Maintenance Therapy in Patients with High Risk Diffuse Large B Cell Lymphoma (DLBCL): Borma Trial from Consortium for Improving Survival of Lymphoma (CISL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2884-2884
Author(s):  
Jae-Cheol Jo ◽  
Ho Sup Lee ◽  
Cheolwon Suh ◽  
Hye Jin Kang ◽  
Won Seog Kim ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
B Cell ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Risk Patients ◽  
Large B Cell Lymphoma ◽  
Risk Patients

Background: High-intermediate or high risk in international prognostic index (IPI) has a long-term chance of cure in the range about 50% in patients with diffuse large B cell lymphoma (DLBCL) treated by R-CHOP. These high risk patients should be considered for additional new treatment to standard R-CHOP or investigational approaches in the context of clinical trials that are designed to ensure that potentially curative therapy. Bortezomib inhibits NF-κB activation through proteasome inhibition, providing rationale for its use in cells that constitutively express NF-κB. Non-germinal center B cell (GCB) DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic NF-κB pathway, which can inhibit chemotherapy. There is no study of bortezomib as maintenance therapy after treated with R-CHOP in high risk patients with DLBCL. So we applied additional bortezomib as maintenance therapy in order to assess improving efficacy and survival rates in high risk patients with non-GCB DLBCL who had been confirmed complete response (CR) after treated with R-CHOP. Methods: Patients with newly diagnosed stage II(bulky)-IV DLBCL with high or high intermediate IPI score of 3 to 5, and patients achieving a CR at the end of 6 or 8 cycles of R-CHOP21 were eligible for enrollment. Non-GCB DLBCL according to Hans criteria confirmed by central review was need before enrollment. Bortezomib maintenance treatment was consisted of bortezomib 1.3mg/m2 subcutaneously administration day 1 and day 15 per 28-day cycle with a total of 12 cycles. The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoints were 3-year overall survival (OS), and toxicites. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Results: Fifty-nine patients were enrolled between May 2014 and Oct 2018. The type of Non-GCB DLBCL in all patients was confirmed by the central pathology review. The median age was 65 years (range: 27-86 years), and 60% were > 61 years. The baseline clinical features were as follows: female sex, 45.8%; ECOG >1, 10.2%; stage II bulky (>10cm), 6.8%; stage III/IV, 93.2%. At the time of analysis, 29 patients completed 12-cycles of bortezomib maintenance, and 3 patients is ongoing. Seven patients did not finished maintenance therapy due to toxicities (fatigue, atrial flutter, neuropathy, pleural effusion, thrombocytopenia), and withdrawal of informed consent (n=4). Sixteen patients experienced disease progression during bortezomib maintenance treatment. With a median follow-up of 25.1 months, 3-year PFS rate was 56.9% and 3-year OS rate was 86.4% (Figure 1). Toxicity was assessed in 489 cycles of bortezomib maintenance in all 59 patients. There was no treatment-related death and febrile neutropenia. Conclusion: Bortezomib maintenance showed 3-year PFS rate of 56.9% with acceptable toxicities in patients with high risk DLBCL achieving a CR at the end of 6 or 8 cycles of R-CHOP21. Figure 1 Disclosures Kim: Celltrion: Research Funding; Novartis: Research Funding; J + J: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

Quality of Life and Overall Survival in High Risk Patients After Radical Cystectomy With a Simple Urinary Derivation

2015 ◽  
Vol 93 (6) ◽  
pp. 368-374
Author(s):  
Giuseppe Mucciardi ◽  
Luciano Macchione ◽  
Alessandro Galì ◽  
Antonina di Benedetto ◽  
Enrica Subba ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Overall Survival ◽  
High Risk ◽  
Radical Cystectomy ◽  
High Risk Patients ◽  
Risk Patients

Newly Diagnosed Myeloma Pateints Are at Risk of Venous Thrombotic Events - High Risk Patients Need To Be Identified and Recieve Thromboprophylaxis: The MRC Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2395-2395
Author(s):  
Faith E. Davies ◽  
J. Anthony Child ◽  
Kim Hawkins ◽  
Susan Bell ◽  
Julia Brown ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
Autologous Transplantation ◽  
High Dose ◽  
Central Venous ◽  
Thrombotic Risk ◽  
Younger Patients ◽  
High Risk Patients ◽  
Increased Risk ◽  
Risk Patients

Abstract Standard treatment for younger patients with presenting myeloma is VAD followed by high-dose melphalan with stem cell support. However this regimen requires a central venous catheter with risks of recurrent line infections and central venous thrombus. A number of oral alternatives have been used including dexamethasone (Dex), thalidomide (Thal) or combinations (Thal/Dex), although to date no randomized control trial has compared an intravenous with oral induction therapy. In older patients melphalan/prednisolone (MP) remains the standard approach. Thal combinations (MPT, CTD, DVdT) improve response rates and providing side effects can be managed effectively may also be appropriate for an elderly population. Patients with myeloma have an increased risk of venous thrombotic events (VTEs), and presenting patients receiving Thal may be at increased risk due to bulk disease. Combination with anthracyclines may also exacerbate this risk. The MRC Myeloma IX trial has been designed to address some of these issues. Younger patients are randomized to receive intravenous CVAD or an oral Thal containing regimen, CTD prior to autologous transplantation; older patients are randomized to MP or the Thal containing regimen, CTDa. At trial initiation (May 2003) physicians were advised that patients should start low-dose Thal (100mg od in the intensive and 50mg od in the non-intensive arm) and slowly dose escalate to 200mg. Patients at high risk of VTE should be considered for full anticoagulation with either warfarin or LMWH. As of Aug 2004 420 patients (239 intensive, 181 non-intensive) have been randomized and a total of 30 VTEs in 28 patients have been reported (22 intensive, 6 non-intensive). In the intensive arm there were 8 DVT, 9 PE and 7 line-related thromboses. In the non-intensive arm there were 4 DVT and 2 PE. CVAD CTD CTDa MP DVT 4.2% 2.5% 4.4% 0% PE 1.7% 5.8% 2.2% 0% Line related 5.0% 0.8% NA NA Total 10.9% 9.1% 6.6% 0% The median time from randomization to DVT/PE was 54.5 days (range 15–113). 4 patients were identified who had additional risk factors (2 immobility, 1 recent operation, 1 renal failure). Only 1 patient was receiving prophylaxis having previously suffered a DVT. There was one PE-related death. Importantly 2 PE and 5 DVT occurred in patients not receiving Thal therapy. All central thrombosis occurred in relation to the central line. In the non-intensive arm the addition of Thal increased VTE risk compared to MP. In conclusion myeloma patients have an increased incidence of VTE (5.9%–8.3%) although in this study so far patients on MP appear to have no excess thrombotic risk. Patients receiving infusional regimes are also at increased risk of line-related events (additional 5.0%). Using the combination of a slowly increasing Thal dose and thromboprophylaxis based on identification of high risk patients the addition of Thal marginally increased DVT/PE risk over and above the risk seen in patients with infusional regimens, but even in a large study such as this the number of events are too small to make firm recommendations. Currently our advice remains unchanged and ALL high risk patients should receive thromboprophylaxis.

A GITIL Prospective Randomized Multicenter Phase III Study of High Dose Sequential Chemotherapy with Rituximab (R-HDS) and Autologous Transplantation (ASCT) of Peripheral Blood Stem Cells Versus CHOP and Rituximab Delivered Every 14 Days (R-CHOP-14) in High-Risk Patients with Diffuse Large B-Cell Lymphomas (DLBCL): Interim Analysis on Feasibility and Toxicity (Protocol R-HDS 0305).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1898-1898
Author(s):  
Sergio Cortelazzo ◽  
Atto Billio ◽  
Alessandro Rambaldi ◽  
Corrado Tarella ◽  
Ingnazio Majolino ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Iii ◽  
Control Group ◽  
High Dose ◽  
Advanced Stage ◽  
Bulky Disease ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Patients ◽  
Ecog Ps

Abstract R-HDS 0305 (Clinical Trials. gov. number NCT00355199) is a multi-centre, unblinded, randomized controlled phase III trial involving 240 patients in 3 years from 16 Italian Cancer Centres, with DLBCL without CNS involvement, advanced stage (stage ≥IIB, bulk), age from 18 to 60 years with ECOG-PS=0–3 and aaIPI=2–3 or age from 61 to 65 years with ECOG-PS=0–2 and IPI 3–5. The control group received R-CHOP-14, which comprised 8 courses of chemotherapy every 14 days, supported by GCSF (day 7–11)±IFRT, if they achieved at least a PR after 4 cycles. Cases refractory to R-CHOP-14 were given R-HDS as salvage therapy. Experimental arm consisted in a R-HDS program, including a debulking phase of 3 courses of doxorubicin-containing chemotherapy (APO), followed by high-dose (HD)-cyclophosphamide (CTX) 7g/sqm, HD-Ara-C (2 g/sqm every 12 hours for 6 days), HD-etoposide 2g/sqm+Cisplatin 100 mg/sqm. After HDS chemotherapy, HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) or a BEAM (BCNU 300 mg/sqm, etoposide 200 mg/sqm, Ara-C 4000 mg/sqm, L-PAM 140 mg/sqm) conditioning regimen with ASCT±IFRT was planned. Rituximab (375 mg/sqm) is given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest, and twice after ASCT. The primary outcomes of the study are complete remission and disease-free survival, overall survival, event-free survival and toxicity. From July 2005 to July 2007, 89 patients were enrolled in the study (R-CHOP-14=43; R-HDS=46). The median age was 51 (range 19–65 years), 11 (12%) had ≥60 years and the M/F was 1.3. Patients presented with adverse features such as advanced stage (88%), BM infiltration (28%), bulky disease (71%), elevated LDH (84%), poor ECOG-PS (55%) and &gt;1 extranodal sites (59%). Until now only 3 patients (3.4%) were refractory to planned treatment: 1/43 (2%) patients belonging to R-CHOP-14 arm shifted to R-HDS salvage treatment and other 2 patients died from lymphoma progression. The main G 3–4 WHO toxicity was haematological: anemia, granulocytopenia and thrombocytopenia occurred in 8%, 18% and 13% of patients, respectively. Grade 2–3 gastrointestinal toxicity and infectious episodes were recorded in 6% and 9% of patients, respectively. Two patients recovered from acute respiratory distress and 2 died of treatment-related toxicity (2.2%). In conclusion, if the R-HDS trial confirms earlier results, preliminary data show that intensive programs such as dose-dense chemo-immunotherapy and R-HDS with ASCT are feasible until 65 years with an acceptable toxic profile, also on the multi-centre basis. At completion of the trial we will assess the role of R-HDS and ASCT on the outcome of high-risk patients with DLBCL.

Screening for Leptomeningeal Disease by High-Sensitivity Flow Cytometry in High Risk Patients with Aggressive Non-Hodgkin’s Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4397-4397
Author(s):  
Joy Mangel ◽  
Jazmin Marlinga ◽  
Mike Keeney ◽  
Jan Popma ◽  
Anargyros Xenocostas ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
High Sensitivity ◽  
B Cell Lymphoma ◽  
Leptomeningeal Disease ◽  
Cns Involvement ◽  
Lymphoma Cells ◽  
High Risk Patients ◽  
Csf Analysis ◽  
Risk Patients

Abstract Background: Central nervous system (CNS) involvement by non-Hodgkin’s lymphoma (NHL) portends a very poor prognosis. There is no consensus in the literature on the “high- risk” features that predict for leptomeningeal disease, and no standardized clinical guidelines exist regarding CNS surveillance, prophylaxis or treatment for patients at increased risk. 2–4 colour flow cytometry (FCM) has been reported to be more sensitive than standard cytology in detecting occult leptomeningeal disease (Blood 2005,105:496). The current study evaluates the utility of a high-sensitivity (5-colour) flow cytometry technique for detecting occult lymphoma cells in the cerebrospinal fluid (CSF) of high-risk patients with NHL. Method: Patients with a new diagnosis of histologically aggressive B or T cell NHL were included in this study if they displayed one or more “high-risk” features for CNS involvement. Patients suspected of CNS relapse of NHL were also eligible for participation. Patients underwent routine staging investigations, with the addition of a diagnostic lumbar puncture (LP) during initial assessment. CSF was tested by standard cytology, cell count and biochemistry, and an additional 5 ml was obtained for analysis by high-sensitivity FCM on a Beckman Coulter FC500. The antibody panel (5 antibodies per tube) was customized according to the phenotype of the lymphoma. The key markers for B cell lymphoma were CD19/kappa/lambda with CD5 or CD10. CD45 was used to identify all white blood cells in the sample. Results: Seventeen patients (8M/9F) with a median age of 59 (range 36–85) have been tested. Patients displayed anywhere from 2–6 “high-risk” features for CNS involvement. These included: HIV positivity (2), primary mediastinal B-cell lymphoma (4), bone marrow (5), multifocal bone (2), paraspinal (1), nasopharyngeal (2) or orbital (1) involvement, elevated serum LDH (12), multiple extranodal sites of disease (5), poor performance status (2), high IPI (3), B-symptoms (9), stage IV disease (11), and otherwise unexplained neurological symptoms (3). 14 patients underwent CSF analysis at time of initial diagnosis, one of whom had cranial nerve palsies secondary to a nasopharyngeal mass extending to the skull base. The other 3 were tested at relapse, transformation, and suspected CNS relapse ultimately diagnosed as a stroke. Despite the presence of these features, CSF analysis was negative for lymphoma cells by both cytology and FCM in all but one of the patients tested. However this patient had very high numbers of circulating lymphoma cells in the peripheral blood (PB), and the positive result was felt to be due to PB contamination of the CSF during a “bloody tap.” One patient with vague neurological symptoms had a negative LP at diagnosis, and later developed frank CNS involvement by lymphoma, but was too unwell to undergo a repeat LP. Conclusions: Given the limited number of patients enrolled thus far and the low prevalence of patients with NHL and CNS involvement (2/17), it is difficult to fully assess the utility of high-sensitivity FCM in the diagnosis of occult leptomeningeal disease. It is of interest that CSF analysis was negative even in the patient with cranial nerve palsies and in the patient who later developed multiple CNS lesions secondary to lymphoma, suggesting that this technique may have limited sensitivity in diagnosing leptomeningeal disease. The systematic screening of high-risk patients cannot yet be recommended as standard clinical practice.

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