Kooperativer Bibliotheksverbund

In: Cancer Medicine, Wiley, Vol. 4, No. 11 ( 2015-11), p. 1754-1766

Abstract: Although most of the mantle cell lymphoma ( MCL ) patients initially responded well to bortezomib (BTZ), the dose‐dependent toxicities have greatly limited the application of BTZ to MCL . To investigate the efficacy and mechanism of arsenic trioxide ( ATO ) with BTZ in inducing apoptosis of MCL cells, two MCL cell lines, along with primary cells from MCL patients ( n  = 4), were used. Additionally, the NOD ‐ SCID mice xenograft model of Jeko‐1 cells was established to study the anti‐ MCL mechanisms in an in vivo setting. ATO treatment highly improved BTZ capacity to inhibit proliferation and induce apoptosis of MCL cells. Furthermore, the interaction of Noxa and Mcl‐1 leads Bak to release from Mcl‐1 or from Bcl‐xl, which could further activate Bak and Bax and then induce cell apoptosis. We also found that when lower doses of BTZ were used in combination with ATO , more effective proapoptotic effects in both the cell lines and the primary cells were obtained compared to the effects of BTZ used alone at higher doses. Simultaneously, the combination of these two drugs delayed the tumor growth in mice more effectively than BTZ alone. The cooperative anti‐ MCL effects of this combination therapy both in vitro and in vivo strongly provided a new strategy to the clinical treatment of MCL .

Type of Medium: Online Resource

ISSN: 2045-7634 , 2045-7634

URL: Issue

URL: Article

DOI: 10.1002/cam4.2015.4.issue-11

DOI: 10.1002/cam4.511

Language: English

Publisher: Wiley

Publication Date: 2015

detail.hit.zdb_id: 2659751-2

In: Experimental Hematology & Oncology, Springer Science and Business Media LLC, Vol. 2, No. 1 ( 2013-12)

Abstract: We previously showed that B-cell receptor (BCR) signaling pathways are important for in vitro survival of mantle cell lymphoma (MCL) cells. To further identify early BCR-activated signaling pathways involved in MCL cell survival, we focused our study on BCR-proximal kinases such as LYN whose dysregulations could contribute to the aggressive course of MCL. Methods Primary MCL cells were isolated from 14 leukemic patients. Early BCR-induced genes were identified by qRT-PCR array. The basal and BCR-induced phosphorylation of LYN and JNK were evaluated by immunoblottting. Cell survival signals were evaluated by apoptosis using flow cytometry. Results We showed that LYN was constitutively phosphorylated in MCL cell lines and in 9/10 leukemic MCL cases. Treatment with dasatinib or with a specific inhibitor of Src kinases such as PP2 suppressed constitutive LYN activation and increased in vitro spontaneous apoptosis of primary MCL cells. BCR engagement resulted in an increase of LYN phosphorylation leading to activation of c-JUN NH2-terminal kinase (JNK) and over-expression of the early growth response gene-1 (EGR-1). Inhibition of JNK with SP600125 induced apoptosis and reduced level of basal and BCR-induced expression of EGR-1. Furthermore, decreasing EGR1 expression by siRNA reduced BCR-induced cell survival. Treatment with PP2 or with dasatinib suppressed BCR-induced LYN and JNK phosphorylation as well as EGR-1 upregulation and is associated with a decrease of cell survival in all cases analysed. Conclusions This study highlights the importance of BCR signaling in MCL cell survival and points out to the efficiency of kinase inhibitors in suppressing proximal BCR signaling events and in inducing apoptosis.

Type of Medium: Online Resource

ISSN: 2162-3619

URL: Article

DOI: 10.1186/2162-3619-2-4

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2013

detail.hit.zdb_id: 2669066-4

In: The Lancet Haematology, Elsevier BV, Vol. 2, No. 6 ( 2015-06), p. e251-e259

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(15)00074-5

Language: English

Publisher: Elsevier BV

Publication Date: 2015

In: The Journal of Pathology: Clinical Research, Wiley, Vol. 7, No. 6 ( 2021-11), p. 604-615

Abstract: Diffuse large B‐cell lymphoma (DLBCL) is a clinically heterogeneous entity, in which the first‐line treatment currently consists of an immuno‐chemotherapy regimen (R‐CHOP). However, around 30% of patients will not respond or will relapse. Overexpression of c‐MYC or p53 is frequently found in DLBCL, but an association with prognosis remains controversial, as for other biomarkers previously linked with DLBCL aggressivity (CD5, CD23, or BCL2). The aim of this study was to explore the expression of these biomarkers and their correlation with outcome, clinical, or pathological features in a DLBCL cohort. Immunohistochemical (c‐MYC, p53, BCL2, CD5, and CD23), morphological (‘starry‐sky’ pattern [SSP]), targeted gene panel sequencing by next‐generation sequencing (NGS), and fluorescence in situ hybridisation analyses were performed on tissue microarray blocks for a retrospective cohort of 94 R‐CHOP‐treated de novo DLBCL. In univariate analyses, p53 overexpression (p53 high ) was associated with unfavourable outcome ( p  = 0.04) and with c‐MYC overexpression ( p  = 0.01), whereas c‐MYC overexpression was linked with an SSP ( p  = 0.004), but only tended towards an inferior prognosis ( p  = 0.06). Presence of a starry‐sky morphology was found to be correlated with better survival in p53 high DLBCL ( p  = 0.03) and/or c‐MYC‐positive DLBCL ( p  = 0.002). Furthermore, NGS data revealed that these three variables were associated with somatic mutations ( PIM1 , TNFRSF14 , FOXO1 , and B2M ) involved in B‐cell proliferation, survival, metabolism, and immune signalling. Taken together, these results show that the SSP pattern seems to be a protective factor in high‐risk DLBCL subgroups and highlight cell death as a built‐in failsafe mechanism to control tumour growth.

Type of Medium: Online Resource

ISSN: 2056-4538 , 2056-4538

URL: Issue

URL: Article

DOI: 10.1002/cjp2.v7.6

DOI: 10.1002/cjp2.223

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 2814357-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 658-658

Abstract: Introduction: We previously reported the results of the PRECIS trial with a median follow-up of 33 months. Both whole brain radiotherapy (WBRT) and autologous stem cell transplantation (ACST) were effective according to the predetermined threshold. However, more relapses occurred in the WBRT arm. The 2-year event-free survival (EFS) from consolidation (relapse or death defined as event) were 69% (95% CI, 57% to 83%) and 87% (95% CI, 77% to 98%) after WBRT and ASCT, respectively (p = 0.03). Overall survival (OS) was similar in both arms. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT. A longer follow-up is required to better assess the impact of the treatment on relapse, survival and late complications. We report here the results of the PRECIS trial with a median follow-up of 98.3 months [min= 4,1 - max= 131.1], focusing on the per protocol population from time of consolidation. Methods: Immunocompetent patients (18 to 60 years of age) with untreated primary CNS lymphoma (PCNSL) were randomly assigned upfront to receive WBRT (Arm A) or ASCT (Arm B) as consolidation treatment after an induction chemotherapy consisting of two cycles of R-MBVP (rituximab, methotrexate, VP16, BCNU, prednisone) followed by two cycles of R-AraC (rituximab, cytarabine). Intensive chemotherapy consisted of thiotepa (250 mg/m2/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/ fraction). Cognitive functions were prospectively assessed until disease progression and focused on global cognitive function, episodic verbal memory, attention and mental flexibility, and psychoaffective status. Results: 140 patients were randomized (Arm A: N = 70; Arm B: N = 70). Fifty-three and 44 patients completed WBRT and ASCT respectively (per protocol population), including 3 and 5 patients who were in progressive disease (PD) at time of WBRT and ASCT, respectively. 8-y EFS from time of consolidation in the per protocol population was 75.9% [63.3-91.0] and 39.9% [26.8-59.3] after ASCT and WBRT, respectively (p = 0.007) (fig 1a). The risk of relapse was significantly decreased after ASCT compared to WBRT (8-y relapse-free interval 94.1% [86.4-100] vs 47.6% [34.2-66.3], (p & lt;0.001) (fig 1b). The 8-year overall survival from time of consolidation was similar in both arms, 63.4% [49.8 - 80.6] and 69.3% [56.7-84.8] in the WBRT and ASCT arms, respectively (fig1c). Among the 24 patients who relapsed after WBRT, 13 patients received subsequent salvage chemotherapy and consolidative ASCT, and seven of these patients were disease-free at last follow-up. Causes of deaths after WBRT (n = 17) were PD (n = 12), neurotoxicity (n = 3), second-line ASCT (n = 2). After ASCT, causes of deaths (n = 14) were treatment-related death (n = 5, including 2 occurring & gt; 100 days post-ASCT, and 2 in patients in PD before ASCT), PD (n = 4), neurotoxicity following salvage WBRT (n = 1), second solid cancer (n = 3) and undetermined in one patient. In multivariate analysis, ECOG, disease status at the end of induction, and protein level in the CSF at diagnosis were independent prognostic factors for OS. Disease status at the end of induction and intraocular involvement at diagnosis were independent prognostic factors for EFS. Cognitive decline that could be fatal was only observed in patients who received WBRT. Imaging analysis of post consolidation leukoencephalopathy is ongoing. Conclusions: Consolidation with ASCT after HD-MTX based induction chemotherapy resulted in an excellent disease control but with a higher treatment-related mortality than WBRT. Severe Cognitive decline and late treatment-induced neurotoxic deaths were observed after WBRT. Intensity of the thiotepa-busulfan-cyclophosphamide regimen used before ASCT should be slightly reduced to improve the benefit/risk ratio of ASCT in first-line treatment of young patients with PCNSL. Figure 1 Figure 1. Disclosures Sylvain: Sanofi, Celegene, Roche, Abbvie, Sandoz, Janssen, Takeda: Consultancy. Damaj: takeda: Consultancy, Honoraria; roche: Consultancy, Honoraria. Sanhes: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146389

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2820-2820

Abstract: On behalf of the Lymphoma Study Association (LYSA) Introduction: Aggressive Mantle Cell Lymphoma variant (A-MCL), including blastic and pleomorphic morphological variants, is a rare subtype of MCL whose frequency varies around 10-15% of all newly-diagnosed MCL patients. According to 2017 World Health Organization (WHO) classification, the diagnosis of A-MCL is based on morphology. A high proliferation rate on Ki-67 staining is not sufficient to be classified as a blastoid or pleomorphic subtype. This might induce diagnostic confusion. The aim of the present retrospective study is to investigate whether or not the CD71, c-Myc, SOX11, P53, ki67 and P16 expressions assessed by immunohistochemistry (IHC) can distinguish A-MCL from classical MCL (C-MCL). We also investigate the prognostic value of these markers in A-MCL patients. Methods: We re-investigated all MCL patients presented with A-MCL (n=110) at diagnosis and who have been enrolled in six prospective clinical trials. At time of inclusion, a centralized pathological review was performed to confirm the diagnosis of MCL. Cases were initially classified according to the 2008 WHO classification (LYMA, MCL-SA, MCL-SJ, RIBVD and RIPAD trials) or according to the 2017 WHO classification (MCLR2-ELDERLY trials). For the present study, we performed a supplemental pathology review by a panel of 5 hematopathologists experts from the LYSA group according to 2017 WHO classification. We identified 75 cases (out of 110) of A-MCL (8 blastic and 67 pleomorphic variants) which represent 15% of all MCL enrolled in these six trials. We have compared A-MCL characteristics to C-MCL who had specimens available for TMA (n=412 C-MCL out of 487 patients enrolled). IHC was performed on TMA, using the six selected antibodies and were scored by quantifying the percentage of cells stained on each spot. Patients available for survival analysis (53 A-MCL and 312 C-MCL) were drawn from all studies (except from the MCLR2-Elderly study that is ongoing). Different cut-offs were considered for progression free survival (PFS) and overall survival (OS) for each variable. The proliferation index was evaluated with Ki67 classical determination eyeballing and Ki67 reading by grid counting. Cut-offs for each of these markers were determined using X-tile software, which determines the optimal value for classifying patients into groups based on overall and progression-free survival. Results: At baseline, the aggressive forms were similar to classical forms in terms of demographic characteristics (age at diagnosis, localization and sex). p53 protein expression was significantly higher in A-MCL patients than in C-MCL (p 〈 0.001) like p16 (p=0.002), c-MYC (p 〈 0.001), CD71 (p 〈 0.001) and Ki67 index (both classical and by grid) (p 〈 0.001). There was no statistically significant difference in SOX11 expression. In univariate analyses, elevated levels of P16 ( 〉 10%), c-MYC ( 〉 30%) Ki67 ( 〉 40%) were associated with poorer OS and PFS in the cohort of A-MCL and C-MCL patients. There was no significant difference in survival both for OS and PFS regarding P53 ( 〉 30%). In multivariate analysis stratified by trial, Ki67 by grid 〉 40% (HR=2.303[1.479-3.585] ; p =0.0002) and c-MYC 〉 30% (HR=1.865 [1.060-3.279] p =0.0305) were predictive for OS whereas only Ki67 by grid 〉 40% (HR=2.055 [1.434, 2.944], p 〈 0.0001) was a significant prognostic factor for PFS. Conclusion: CD71, c-Myc, P53 and P16 expression levels assessed by IHC are higher in A-MCL as compared to C-MCL. These markers could therefore be recommended in routine practice to distinguish between A-MCL and C-MCL. We also found that patients with Ki67 count by grid 〉 40% had significantly shorter PFS and OS and patients with high Myc expression 〉 30% had a significantly poorer OS. Thus, MYC expression and Ki67 by IHC is a suitable test for routine diagnostic practice to assess A-MCL prognosis. Disclosures Le Gouill: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Ribrag:argenX: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dreyling:Novartis: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau. Hermine:Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129790

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3450-3450

Abstract: Unavailability of Carmustine and its dramatically increased cost by nearly 10 fold has led to its replacement by bendamustine (Be) and an increase use of Bendamustine-based (BeEAM) conditioning regimen before autologous stem cell transplantation for lymphoma. The aim of this study was to evaluate the safety of the BeEAM regimen in the real life use in several French centers. Median age of the 386 patients (233 male, 153 female) was 55 years (17-72). The majority of patients had aggressive B-cell (40%), follicular (17%), Hodgkin's (17%) and mantle cell lymphoma (15%). Two hundred and forty six patients (64%) were transplanted after 2nd line chemotherapy and the median number of prior lines of chemotherapy of 2 (1-9). Two hundred and sixty patients (67%) had received prior platinum chemotherapy and only 4% had a history of prior chronic renal failure (Table 1). The median creatinine level at conditioning initiation was 71(36-206) µmol/l. Be was administered at a median dose of 191 mg/m2/day (50-250) on day -7 and -6. Thirty two percent received 100-160 mg/m²/d and 58% of patients received more than 160 mg/m²/d. Median 24h-hydration volume was 3 l (1-6) which began within median time of 18 h (1-72) prior to conditioning initiation. The median duration time of Be perfusion was 60 min (30-143). Grade 1-4 acute renal failure (ARF) was reported in 107 cases (28%) (G ≥2; 34%) and appeared after a median time of 2 days (1-18) after conditioning start. Melphalan dosage was reduced, due to renal failure, in 10% of patients (Table 2). 84% of patients normalized their creatinine level within a median time of 10 days (1-77). The most frequent reported Grade 1-4 toxicities were mucositis (84%), gastroenteritis (53%), skin toxicity (34%), colitis (29%), liver toxicity (19%), pneumonitis (5%) and cardiac rhythm disorders (4%). Opportunistic infection was documented in 9.5% of patients, HHV6 reactivation in 6% of patients. Ten percent of patients needed intensive care management and toxic death was estimated at 5% (Table 3). Patients received a median of 3 (0-34) packed red blood cells and 4 (0-56) platelets units. The median time to neutrophils 〉 0.5 G/L and platelets 〉 20 G/L were 10 (0-50) and 12 (0-210) days. The median time of hospital stay was 23 (12-85) days. In comparison with the group of patient without renal failure, the group of patients with ARF had older age (58 vs 54), higher rate of pre-transplant chronic renal failure (10% vs 1%), higher rate of platinum treatment (77% vs 64%), higher day1 creatinine level (81 vs 69) and received higher median bendamustine (199 vs 182). Colitis (p=0.039), pneumonitis (p=0.008), cardia arrhythmia (p= 〈 0.0001), intensive care admission (p= 〈 0.0001), need for blood transfusion (p= 〈 0.0001), hospital stay duration (p= 〈 0.0001), and death (p= 〈 0.0001), were more frequent in patients with post conditioning renal failure. In multivariate analysis, creatinine level at day1, bendamustine dose 〉 160mg/m2 and age were independent prognostic factors for ARF. A three-point clinical predictor score for acute renal failure was identified and included creatinine level 〉 65µmol/l, bendamustine dose 〉 160mg/m² and age 〉 57 years. ARF stratified by score, was 4% with score 0, 17% with score 1, 30% with score 2 and 45% with score 3. In conclusion, BeEAM induced 5% non-relapse mortality with high rate of renal toxicity. A simple, three-point scoring system can stratify patients by levels of risk for ARF. Rapid identification of higher risk patients may allow a reduction of the bendamustine dose to improve clinical outcomes. Prospective comparative studies are needed to confirm toxicity extents of this conditioning as compared with other type of high dose therapy. Disclosures Soussain: Pharmacyclics: Research Funding; Celgene: Research Funding; Roche: Research Funding. Malak:Novartis: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3450.3450

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 784-784

Abstract: RATIONAL Primary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype, carrying a pejorative prognosis. Constitutive activation of the NF-kB pathway via mutations in B cell receptor (BCR) pathway (CD79B) and mutation of MYD 88 and TBL1XR1 plays an important role in PCNSL. Ibrutinib, an inhibitor of BCR signaling, has been found to have significant therapeutic activity in relapsed or refractory non-CNS non-GC DLBCL. METHODS In this prospective, multicenter, open-label phase II, we enrolled immuno-competent patients over 18 with a refractory or relapse of PCNSL or primary vitreo-retinal lymphoma (PVRL) of DLBCL type. The treatment consisted in ibrutinib monotherapy given orally at 560 mg daily until disease progression or unacceptable toxicity. Additional corticosteroids treatment was allowed during the first 4 weeks of treatment in case of a threatening or symptomatic edema. Therapeutic responses were assessed according to the international primary CNS lymphoma collaborative group (IPCG) criteria. The primary objective of the study was the disease control (DC) rate (CR + CRu + PR + SD) after two months of treatment. This study is a two-stage Simon's design. Patients were evaluable for response if they received 〉 90 % of the expected dose during the first month of treatment. An interim analysis for futility was planned when 18 patients were evaluable for response. P0 and P1 hypotheses were 〈 10 % and 〉 30 % respectively. A total of 35 evaluable patients are required for the final analysis. Exploratory ancillary studies are planned and consist in dosage of ibrutinib in the cerebrospinal fluid after one cycle of treatment, and correlation of therapeutic response with mutational status of the disease. This study is registered with ClinicalTrials.gov, number NCT02542514. RESULTS BetweenSeptember 25, 2015 and June 30, 2016, 52 patients were recruited in 10 French centers of the French LOC network for PCNSL. The interim analysis was done on the first 18 patients evaluable for response (median age: 70 y, range 49-80). At initial diagnosis, diagnoses were PCNSL (n = 12) and PVRL (n = 6). Patients were included in the study for a relapse (n = 13) or a progressive disease (n = 5). At time of inclusion in the study, disease status was PCNSL (n = 11) and PVRL or isolated intra-ocular relapse of a PCNSL (n = 7). ECOG performance status was 0, 1 and 2 in 4, 10 and 4 patients respectively. All the patients had previously received high-dose methotrexate-based chemotherapy. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplantation. Patients had received 1, 2 or 3 prior treatments in 12, 5 and 1 cases respectively. Three patients had a concomitant meningeal involvement. Five patients received concomitant corticosteroids during the first month of treatment. At the time of analysis (median follow-up = 6.6 months), nine patients discontinued ibrutinib after a median duration of 3 months (range, 0.9 -6.4) because of a disease progressive(n = 8) or a concurrent illness (n=1). Median number of treatment cycles was 5 (range, 1-9). One patient experienced a pulmonary aspergillosis with a favorable outcome. No hemorrhagic complication was reported. Five patients died due to disease progression (n = 4), and concurrent illness (n = 1). After two months of treatment, a DC was achieved in 15/18 patients (83 %, IC 95 %, [59-96%] ) (complete and unconfirmed complete response: n =3; partial response: n = 7; stable disease: n =5). CONCLUSION In this interim analysis, Ibrutinib monotherapy demonstrated a high DC rate of 83%, including 56% objective responses in patients with relapse/refractory PCNSL or PVRL. Regarding safety, Ibrutinib might be a risk factor for aspergillosis in this population of PCNSL patients, otherwise not exposed to fungal infection. A security warning was sent to all the investigators for a close monitoring of infections. The second cohort of patients has been recruited. Thirty-three patients are currently on study treatment. The final analysis of the iLOC study is awaited to confirm these encouraging results and better define the positioning of ibrutinib in the therapeutic strategy of PCNSL and PVR patients. Disclosures Choquet: Janssen: Consultancy; Celgene: Consultancy. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Soussain:Celgene: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.784.784

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 1490-1490

Abstract: When patients (pts) with newly diagnosed multiple myeloma (MM) are treated with autologous stem cell transplantation (ASCT), the standard induction therapy is a dexamethasone (Dex) based regimen. Currently, the use of VAD or Dex alone results in a complete remission (CR) rate of 〈 10%. In an ongoing ECOG trial comparing Dex alone to the combination thalidomide plus Dex, preliminary results did not show a clear advantage of the combination (Rajkumar ASCO 2004). Since achievement of CR is a major objective in the treatment of MM, better therapeutic regimens are being investigated. Bortezomib is currently approved in the US and in the EU for the treatment of relapsed/refractory MM. Both in vitro studies and preliminary clinical experience in relapsed/refractory pts have suggested that the combination of bortezomib and Dex could further improve the results achieved with bortezomib alone. The IFM group initiated a Phase II open trial assessing the combination of bortezomib and Dex in pts with previously untreated MM and who are candidates for ASCT. The regimen consisted of bortezomib 1.3mg/m² iv on days 1, 4, 8, 11 and Dex 40 mg per os days 1–4, 9–12 (for the first 2 cycles, days 1–4 only for the last 2 cycles), administered on 4 consecutive 21 days cycles. Stem cell collection was performed just before cycle 4 after G-CSF priming. The primary objective of the study was CR rate after 4 cycles. As of August 1, 47 pts have been recruited and data is available for the first 18 pts. The median age is 53 years (38–63) Sixteen / 18 pts received 4 cycles: 1 patient progressed after 3 cycles and in one case the last two injections of bortezomib were not performed because of grade 3 neuropathy. The overall results were as follows: CR (negative electrophoresis) 3; very good partial remission (90% reduction of M component) 2; partial remission (50% reduction of the serum M component or 90% reduction of the urine M component) 10; failure (stable disease or progression ) 3. The overall response rate was 83% and the CR rate was 17%. Side effect were usually mild (grade 1/2); only one grade 3 neuropathy was recorded. In all cases stem cells could be adequately collected. These preliminary results appear to be very encouraging and the bortezomib / Dex combination appears effective and well tolerated in pts with newly diagnosed MM. The results will be updated at time of presentation. If updated analysis confirms currently available data, the IFM will start a large randomized phase III trial comparing VAD and bortezomib / Dex as induction treatment prior to ASCT in pts with newly diagnosed MM up to the age of 65.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V104.11.1490.1490

Language: English

Publisher: American Society of Hematology

Publication Date: 2004

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 335-335

Abstract: INTRODUCTION. FGD-PET has emerged as an important predictor of clinical outcome in lymphomas. However, its utility in everyday clinical practice in mantle cell lymphoma (MCL) remains uncertain because there is a lack of large prospective trials including FDG-PET results. To address this question, we conducted the LyMa-MRD project as an ancillary study in a prospective phase III trial in MCL (NCI NCT00921414; LyMa Trial). From Sept 2008 to Aug 2012, 299 previously untreated MCL patients ( & lt;66yrs) were enrolled in the LyMa trial (a phase III international prospective trial, NCT00921414). Briefly, all patients received 4 courses of R-DHAP followed by ASCT using an R-BEAM conditioning regimen (n=257). After ASCT, patients were randomized between observation (obs) (n=120) versus Rituximab maintenance (RM) (n=119). The first planned interim-analysis, with a median follow-up of 40.6 months was presented at ASH 2014 and indicated superior progression-free survival (PFS) in the RM versus Obs arms (Le Gouill et al. ASH 2014). Sequential FDG-PET monitoring was optional and a predefined secondary objective and was performed throughout. Treatment strategy was not modified by FDG-PET results. Indeed, the population of the LyMa trial is the ideal population to investigate the predictive power of FDG-PET parameters at diagnosis and after induction in MCL. Herein, we present the first results performed from the database of first planed interim-analysis. METHOD. FDG-PET of 94 MCL patients have been independently and centrally reviewed by 2 lymphoma expert nuclear physicians. Quantitative metrics including SUVmax, SUVmean, SUVpeak, total lesion glycolysis (TLG) were extracted from the area with the highest uptake, at diagnosis and before ASCT (iPET). Visual analysis by the Deauville scale was also performed at iPET. The best cut-off values were determined for each metric using X-tile® analysis. Prognostic value was assessed using univariate analysis by Kaplan-Meier estimates of PFS. RESULTS. The studied population did not differ from the whole population of the LyMa trial (baseline characteristics, demographic data, staging, balance between observation vs maintenance and outcome). At diagnosis, univariate analysis showed a prognostic value on PFS of 4 metrics: SUVmax (p & lt;0.001), SUVmean (p & lt; 0.001), SUVpeak (p & lt;0.001), TLG (p=0.03). The best cut off for these 4 indices, were 11.4, 7.7, 8.7, and 65 respectively. Indeed, median PFS was not reach (NR) for patients with low SUVmax (n=63) as compared to only 26.3 months for patients with high SUVmax (p & lt;0.0001) (n=31). Results were similar for SUVpeak, SUVmean and TLG. The prognostic value of SUVmax was reinforced when combined with MIPI. Indeed, patients can be separated in 3 prognostic groups including a group of patients with a very good outcome (low SUVmax plus MIPI inter/low). Results of iTEP showed that ΔSUV before ASCT (defined as a decrease of SUVmax values from diagnosis to end of induction & gt; 29.65%) was predictive of PFS: median NR vs 42.3m (p=0.0051). In contrast FGD-PET before ASCT according to Deauville scale was only predictive for score 5 vs 1/2/3/4. Conclusion. The LyMa-PET project is the largest study addressing the question of FDG-PET in a homogeneously treated population of MCL. It shows for the first time that SUVmax ( & lt;/ & gt;11.4) at diagnosis and ΔSUV ( & lt;/ & gt;29.65%) provide predictive parameters for outcome in MCL. Update results and patients' outcome according to randomization arms will be updated for the time of the meeting. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.335.335

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7