Thalidomide/Dexamethasone (TD) Vs. Bortezomib(Velcade®)/Thalidomide/Dexamethasone (VTD) Vs. VBMCP/VBAD/Velcade® As Induction Regimens Prior Autologous Stem Cell Transplantation (ASCT) in Younger Patients with Multiple Myeloma (MM): First Results of a Prospective Phase III PETHEMA/Gem Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 654-654 ◽  
Author(s):  
Laura Rosinol ◽  
M. Teresa Cibeira ◽  
Joaquin Martinez ◽  
Maria Victoria Mateos ◽  
Ma José Terol ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Induction Therapy ◽  
Statistical Significance ◽  
Phase Iii ◽  
Induction Phase ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Intention To Treat ◽  
The Difference ◽  
Grade 3

Abstract The benefit of ASCT in MM is associated with the degree of tumour decrease with the initial induction chemotherapy. In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Velcade® in patients 65 years-old or younger with newly diagnosed symptomatic MM, followed by ASCT with MEL-200. The primary end points were response rate after induction and after ASCT and time to progression. TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus Velcade 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus Velcade® consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of Velcade® (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. Two-hundred and seventy-five out of the 390 planned patients have been included so far. As of February 15, 2008, 190 patients (median age: 57 yrs., M:96, F:94; IgG:107, IgA:50, light chain:25, others:9) entered the study. 32 (17%) patients had soft-tissue extramedullary plasmacytomas (EMP) and the stage according to the ISS classification was I in 38%, II in 41%, III in 20% and unknown in 1%. The prognostic factors, including cytogenetics, were similar in the 3 arms. The prognostic factors, including cytogenetics, were similar in the three arms. 173 patients (TD:61, VTD:54 and VBMCP/VBAD/Velcade:58) were already evaluable for response and toxicity to induction therapy. Efficacy and toxicity were assessed on an intention-to-treat basis. The ≥PR rate was 62%, 77% and 70% with TD, VTD and VBMCP/VBAD/Velcade®, respectively (p=NS). The IF negative CR rate was significantly higher with VTD (31%) and with VBMCP/VBAD/Velcade® (22%) compared to TD (6%) (p< 0.01). Progressive disease was significantly higher in patients with EMP (31% vs. 12%, p=0.01). This higher PD rate in patients with EMP was similar in the three arms. The incidence of grade 3 and 4 adverse events (AEs) was 38%, 54% and 50% with TD, VTD, and VBMCP/VBAD/Velcade® respectively. The total number of AEs for TD, VTD and VBMCP/VBAD/Velcade® were 37, 36 and 44, respectively. 13% of patients receiving TD developed ≥ grade 3 thrombotic events while 16% of patients in the VTD arm had grade ≥3 peripheral neuropathy. Treatment discontinuation due to toxicity was required in 8 patients (TD: 1; VTD: 5, VBMCP/VBAD: 2). 5 patients died during the induction phase (TD:3, VTD:0, VBMCP/VBAD/Velcade:2). 72 patients were evaluable for response after ASCT. The post-ASCT CR rate were higher with VTD (50%) and with VBMCP/VBAD/Velcade® (39%) compared to the TD arm (26%), although the difference did not reach statistical significance. Our preliminary analysis shows that VTD and VBCMP/VBAD plus Velcade® result in a higher CR rate than TD both before and after ASCT and that the toxicity in the three arms is not significantly different. Longer follow-up is needed to establish whether or not this higher tumour reduction is translated into a significant better long-term outcome. Updated results will be presented at the meeting.

Characteristics and Outcome Of 66 Patients With Extramedullary Plasmacytomas (EMPs) Included In a Phase III Pethema/GEM Study Of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3188-3188
Author(s):  
Laura Rosiñol ◽  
Raquel Jiménez-Segura ◽  
Ana Isabel Teruel ◽  
Javier De La Rubia ◽  
Maria Victoria Mateos ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Statistical Significance ◽  
Phase Iii ◽  
Advisory Committees ◽  
Intention To Treat ◽  
Extramedullary Disease ◽  
The Difference ◽  
Extramedullary Plasmacytomas

Abstract Introduction In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) initiated a randomized phase III trial (GEM05menos65) comparing induction with thalidomide/dexamethasone (TD) vs. bortezomiv/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200 and maintenance therapy with interferon vs, thalidomide alone or bortezomib/thalidomide. The results of the overall series has been previously published. However, the efficacy of novel agents in patients with extramedullary disease is not well stablished. Primary end points to describe the characteristics and outcome of patients with EMPs homogeneously treated in the GEM05menos65 trial. Patients and Methods TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1-4 and 9-12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus i.v. bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of i.v. bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. 66 patients (17%) had extramedullary plasmacytomas (median age: 54 years, M: 33, F: 33). The isotype was IgG: 41, IgA 11, Bence-Jones: 10, IgD:4; kappa:41, lambda: 25.The stage according to the ISS was I in 27 patients, II in 26 and III in 13 patients. The location of the EMPs was soft-tissue masses arising from lytic lesions in 60 patients, testicular mass with no contact with bone in 1 case and was not specified in 6 cases. Nine patients had multiple extraosseous plasmacytomas. 17 patients received induction therapy with VBMCP/VBAD/B, 23 with TD and 26 with VTD. Results Cytogenetic information was available in 51 out of the 66 cases with EMPs and 12 of them (23%) showed high-risk cytogenetics. There were no differences in the incidence of high-risk cytogenetics (t(4;14), t(14;16) and del 17p) in patients with and without EMPs (23% vs 21%). The incidence of t(4;14) in patients with and without EMP was 16% vs 23%, respectively. The incidence of del 17p was 10% and 6% in patients with and without EMPs.The IFE negative CR rate was significantly higher with VTD as compared to TD (42% vs 13%, p=0.02) while there was no significantly differences among VTD and VBMCP/VBAD/B (42% vs 29%, p=NS). Patients with EMP had a significantly higher rate of PD during induction therapy as compared to patients without EMPs (24% vs 11%, p=0.01). This higher rate of PD in patients with EMP was observed in the 3 induction arms (VBMCP/VBAD/B 24% vs 9%, TD 40% vs 19%, VTD 12% vs 6%). 43 patients received ASCT as part of the treatment design. On an intention to treat basis, the pos-ASCT CR rate was higher with VTD arm compared to TD (50% vs 22%, p=0.07) but not significantly different from VBMCP/VBAD/B (50% vs 41%, p=0.7). After a median follow-up of 46 months, there was no significant differences in PFS between patients with or without EMP (26.9 vs 39.9 months, p=0.47). Although the difference did not reach statistical significance, there was a trend towards a shorter PFS for patients with EMPs with high-risk cytogenetics (median 12.1 vs. 28.3 months, p=0.13). In patients with EMPS, the PFS was not reached in the VTD arm versus 26.9 months with VBMCP/VAB/B and 22.8 moths with TD. The OS was significantly shorter in patients with EMPs as compared to patients without EMPs (median 69.9 months vs not reached, p=0.02) Conclusion 1) In the present study the frequency of EMPs was 17%, 2) the incidence of high-risk cytogenetics in patients with EMPs was similar to that observed in patients with no extramedullary disease, 3) patients with EMPs had a higher rate of progressive disease irrespective of the induction arm as compared to patients without EMPs, being VTD the best treatment option, 4) finally, the OS was significantly shorter in patients with EMPs. Disclosures: Rosiñol: Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Mateos:Jansen: Honoraria; Celgene: Honoraria. Tomas:MedImmune: Research Funding. Gutiérrez:Jansen: Honoraria; Celgene: Honoraria. San Miguel:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

Thalidomide / Dexamethasone (TD) Vs. Bortezomib (Velcade)â/Thalidomide / Dexamethasone (VTD) Vs. VBMCP/VBAD/Velcadeâ as Induction Regimens Prior Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM): Results of a Phase III PETHEMA/GEM Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 130-130 ◽  
Author(s):  
Laura Rosiñol ◽  
Ma Teresa Cibeira ◽  
Joaquin Martinez ◽  
Maria Victoria Mateos ◽  
Albert Oriol ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
High Risk Group ◽  
Phase Iii ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Phase Iii Trial ◽  
Grade 3

Abstract Abstract 130 In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Velcadeâ in patients 65 years-old or younger with newly diagnosed symptomatic MM, followed by ASCT with MEL-200. The primary end points were response rate after induction and after ASCT and time to progression. TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus Velcade 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus Velcadeâ consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of Velcadeâ (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. As of December 31, 2008, 305 patients (median age: 57 yrs, M: 156, F:149; IgG. 181, IgA: 71, light chain: 43, others: 10) entered the study and are the basis of the current analysis. Fifty-six (18%) patients had soft-tissue extramedullary plasmacytomas (EMP) and the stage according to the ISS was I in 39%, II in 41 %, III in 19 % and unknown in 1%. The prognostic factors, including cytogenetics, was similar in the 3 arms. Fifty-five (18%) patients had high-risk cytogenetics (t(4;14), t(14;16) and/or 17p deletion). Two-hundred and ninety-nine patients (TD:103, VTD: 99 and VBMCP/VBAD/Velcade®: 97) were evaluable for response and toxicity to induction therapy. The ≥ PR rate was 64%, 82% and 75% with TD, VTD and VBMCP/VBAD/Velcade®, respectively (p=NS). The IF negative CR rate was significantly higher with VTD (29%) and with VBMCP/VBAD/Velcade® (25%) than with TD (14%) (p=0.009 and p=0.04, respectively). Progressive disease (PD) was significantly higher with TD than with VTD (21% vs. 8%, p=0.009). In the overall series, PD was significanty higher in patients with EMP (34% vs. 12%, p=0.0002) with a significanty higher PD rate for TD as compared with VTD (40% vs. 14%, p=0.05). In patients with poor cytogenetics the CR rate was significantly higher with VTD than with TD (42% vs. 5%, p=0.009). In this high-risk group the PD rate was higher with TD (37%) and with VBMCP/VBAD/Velcade® (23%) than with VTD (0%) (p=0.009 and p=0.04, respectively). The incidence of thrombotic events ≥ grade 3 was higher in the TD arm (9% vs. 1% vs. 3%, p=0.07 and p=0.01) while ≥3 peripheral neuropathy was higher with VTD (14% vs. 0% and 1%, p<0.0001 and p=0.0003). Treatment was discontinued due to toxicity in 11 patients (TD: 3, VTD: 6, VBMCP/VBAD/Velcade®:2). Eight patients died during induction period (TD:5, VTD: 2, VBMCP/VBAD/Velcade®: 1) One-hundred seventy-seven patients were evaluable for response after ASCT. The post-ASCT CR rate with TD, VTD and VBMCP/VBAD/Velcade® was 40%, 59% and 48%, respectively, being significantly higher with VTD than with TD (p=0.05). The estimated overall survival at 2 years is 82% with no significant differences among the 3 arms. TTP and PFS were significantly shorter with TD (p=0.05 and p=0.012, respectively). In summary, VTD results in a higher pre- and post-ASCT CR rate as well as in a lower PD rate than TD, particularly in patients with high-risk cytogenetics or with EMP. The TTP and PFS are shorter with TD. Intermediate results are observed with VBMCP/VBAD/Velcade®. Longer follow-up is needed to establish whether or not these results will translate into a significantly different long-term outcome. Updated data will be presented at the meeting. Disclosures: Rosiñol: Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Thalidomide and bortezomib are not yet approved in Spain. Cibeira:Jansse-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. de la Rubia:Janssen-Cilag: Honoraria; Celgene: Honoraria. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Honoraria; Celgene: Honoraria.

SWOG S1216: A phase III randomized trial comparing androgen deprivation therapy (ADT) plus TAK-700 with ADT plus bicalutamide in patients (pts) with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) (NCT01809691).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5001-5001
Author(s):  
Neeraj Agarwal ◽  
Catherine Tangen ◽  
Maha H. A. Hussain ◽  
Shilpa Gupta ◽  
Melissa Plets ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Performance Status ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Meaningful Improvement ◽  
Intention To Treat ◽  
Grade 3

5001 Background: Tak is an oral selective nonsteroidal 17, 20-lyase inhibitor that blocks the synthesis of gonadal and adrenal androgens. We evaluated the clinical benefit of Tak with ADT in pts with newly diagnosed mHSPC. Methods: Pts with mHSPC with a Zubrod performance status (PS) of 0-2 and a PSA of ≥ 2 ng/ml were randomized 1:1 to ADT+Tak (300 mg twice daily) or ADT+Bic (50 mg daily). Stratification factors included PS (0-1 vs ≥2), extent of disease (minimal vs extensive), and receipt of ADT prior to registration (yes vs no). The primary endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS; based on PSA, imaging or clinical progression), PSA at 7 months (≤0.2 vs 0.2 < PSA; ≤-4 vs. > 4 ng/ml) and adverse event (AE) profile. With 2.75 yrs to accrue 1,186 eligible pts and 3 additional yrs of follow-up, we would have 90% power to determine a 33% improvement in OS from 54 to 72 mos (1-sided α = 0.025). A final analysis was pre-specified after 523 deaths using a 1-sided α = 0.022 to account for interim analyses. Results: Between 3/2013 and 7/2017, 1,313 pts were randomized and 1,279 were included in the intention-to-treat (ITT) analysis (32 pts were ineligible and 2 pts withdrew consent). Median age was 68 yrs and 10% of subjects were Black. Median PSA was 30 ng/mL (range 2-6710) and 49% of pts had extensive disease. After a median follow-up of 4.9 yrs, PFS and PSA response were significantly improved with Tak over Bic but no significant improvement in OS was observed (Table). More grade 3/4 AEs occurred in Tak vs. Bic arms (43% vs. 14%), and included hypertension (20% vs. 5%) and fatigue (5% vs. 2%). Five pts in Tak and 1 pt in the Bic arm had grade 5 AE. Conclusions: Despite clinically meaningful improvement in various outcome measures with Tak+ADT over Bic+ADT in this representative population of mHSPC, the improvement in OS did not meet the pre-specified criteria for statistical significance. The median OS of 70 mos in the control arm (standard ADT) was higher than that reported in contemporary phase 3 trials in this setting, and 16 mos higher than originally estimated. This trial sets a new landmark for survival estimates when pts with mHSPC have access to multiple approved subsequent life-prolonging therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820; U10CA180821; and in part by Millennium Pharmaceuticals, Inc. (Takeda Pharmaceutical Company LTD) Clinical trial information: NCT01809691. [Table: see text]

Rituximab Maintenance Treatment of Relapsed/Resistant Follicular Non- Hodgkin’s Lymphoma: Long-Term Outcome of the EORTC 20981 Phase III Randomized Intergroup Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 836-836 ◽  
Author(s):  
Marinus H.J. Van Oers ◽  
Martine Van Glabbeke ◽  
Liliana Baila ◽  
Livia Giurgia ◽  
Richard Klasa ◽  
...  
Keyword(s):  
Maintenance Treatment ◽  
Statistical Significance ◽  
Recurrent Infection ◽  
Maintenance Phase ◽  
Phase Iii ◽  
Remission Induction ◽  
Term Outcome ◽  
Long Term Outcome

Abstract Background. In 2005 we analyzed the results of a prospective randomized phase III intergroup trial evaluating the role of rituximab (R) both in remission induction and maintenance treatment of 465 relapsed/resistant follicular lymphoma (FL) patients. Major conclusions were that addition of R to CHOP induction yielded an increased ORR and CR rate, and that R maintenance strongly improved median progression free survival (PFS), both after induction with CHOP and R-CHOP, and overall survival (OS (van Oers et al Blood2006;108:3295). At that time the median follow for the maintenance phase was 33 months. Now we report the long-term outcome of maintenance treatment, with a median follow up of 6 years from start of maintenance. Study design. Patients with stages III or IV FL at initial diagnosis and relapsed after or resistant to a maximum of two non-anthracycline containing systemic chemotherapy regimens, were randomized to remission induction with either 6 cycles of standard CHOP (once every 3 weeks) or CHOP + R (375 mg/m2 at day 1 of each cycle of CHOP). Those with a complete or partial remission after 6 cycles of therapy underwent a second randomization to no further treatment (observation) or maintenance treatment with R (375 mg/m2 once every 3 months) until relapse or for a maximum period of two years. Results. 465 patients were randomized to induction with either CHOP (231) or R-CHOP (234). As reported, CHOP and R-CHOP induction yielded similar partial response rates (57% vs.56%), but significantly different CR rates (16% and 29%; p=0.0001). 334 patients were randomized to either R maintenance treatment (167) or observation (167). R maintenance resulted in a highly significant improvement of PFS: median 3.7 years versus 1.3 years in the observation arm (p<0.0001; hazard ratio 0.55). The advantage of R maintenance was observed both after CHOP induction (p< 0001: HR 0.37) and R-CHOP induction (p= 0.003; HR 0.69). The 5 years OS was 74% in the R maintenance arm and 64 % in the observation arm (p=0.07). That the highly improved PFS after R maintenance did not translate into a significant OS advantage might partially be explained by the fact that 41% of progressing patients received R as salvage therapy. This varied according to treatment arm: from 59% after CHOP followed by observation to 26% after R-CHOP followed by R maintenance. R maintenance was associated with a significant increase in grade 3/4 infections: 9.7% vs.2.4% (p= 0.01). 7 of the 167 patients had to discontinue R maintenance because of toxicity, mostly recurrent infection. Conclusion. With long term follow-up we confirm the superior PFS with R maintenance. The improvement of OS did not reach statistical significance, possibly due to the abundant use of R in post-protocol salvage treatment.

scholarly journals Spinal Hemangioblastomas: Analysis of Surgical Outcome and Prognostic Factors

2021 ◽  
Author(s):  
Alberto Feletti ◽  
Alessandro Boaro ◽  
Davide Giampiccolo ◽  
Giorgio Casoli ◽  
Fabio Moscolo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Neurological Outcome ◽  
Statistical Significance ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Neurological Condition ◽  
Before And After ◽  
Vhl Disease ◽  
The Impact

Abstract Background. The prognostic factors for surgically removed spinal hemangioblastomas, the impact of VHL disease on outcome, and the role of intraoperative neuromonitoring are still not completely clear. The aim of this study was to review our experience with spinal hemangioblastomas in order to assess potential predictors of neurological outcome after surgery.Methods. All cases of spinal hemangioblastomas removed at two Italian academic institutions from 1985 to 2020 were reviewed. Data about clinical presentation and symptoms duration, diagnosis of VHL, surgical approach, use of IONM, duration of hospital stay, follow up, McCormick grade before and after surgery were extracted.Results. Sixty-one patients (31 F, 30 M) underwent 69 surgeries to remove 74 spinal hemangioblastomas (37 cervical, 32 thoracic, 5 lumbar). Improvement was found in 32.3% of cases, neurological condition remained stable in 51.6% of cases, and deteriorated in 16.1% of patients.A worsening trend in VHL patients and an improvement trend in non-VHL patients were detected, despite the lack of statistical significance. Laminotomy and use of IONM were found to be associated with better outcome, although no association was found between surgery without IOM and worse outcome.Conclusion. In most cases, patients affected by spinal hemangioblastomas can expect a good long-term outcome. In our experience, laminotomy seems to be associated with better outcome compared to laminectomy. While its absence is not associated with worse outcome, IONM seems to be associated with a better neurological outcome. Our study suggests that the more impaired the preoperative neurological condition, the worse the outcome.

scholarly journals Rituximab Maintenance Treatment of Relapsed/Resistant Follicular Non-Hodgkin's Lymphoma: Long-Term Outcome of the EORTC 20981 Phase III Randomized Intergroup Study

2010 ◽  
Vol 28 (17) ◽  
pp. 2853-2858 ◽  
Author(s):  
Marinus H.J. van Oers ◽  
Martine Van Glabbeke ◽  
Livia Giurgea ◽  
Richard Klasa ◽  
Robert E. Marcus ◽  
...  
Keyword(s):  
Maintenance Treatment ◽  
Statistical Significance ◽  
Maintenance Phase ◽  
Phase Iii ◽  
Remission Induction ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Rituximab Maintenance

Purpose In 2006, we published the results of the European Organisation for Research and Treatment of Cancer phase III trial EORTC 20981 on the role of rituximab in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). At that time, the median follow-up for the maintenance phase was 33 months. Now, we report the long-term outcome of maintenance treatment, with a median follow-up of 6 years. Patients and Methods Overall, 465 patients were randomly assigned to induction with either six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab plus CHOP (R-CHOP). Those in complete remission or partial remission after induction (n = 334) were randomly assigned to maintenance treatment with rituximab (375 mg/m2 intravenously once every 3 months) or observation. Results Rituximab maintenance significantly improved progression-free survival (PFS) compared with observation (median, 3.7 years v 1.3 years; P < .001; hazard ratio [HR], 0.55), both after CHOP induction (P < .001; HR, 0.37) and R-CHOP (P = .003; HR, 0.69). The 5-year overall survival (OS) was 74% in the rituximab maintenance arm, and it was 64% in the observation arm (P = .07). After progression, a rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance. Rituximab maintenance was associated with a significant increase in grades 3 to 4 infections: 9.7% v 2.4% (P = .01). Conclusion With long-term follow-up, we confirm the superior PFS with rituximab maintenance in relapsed/resistant FL. The improvement of OS did not reach statistical significance, possibly because of the unbalanced use of rituximab in post-protocol salvage treatment.

Bortezomib (Velcade®)-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) in Preparation for Autologous Stem-Cell (SC) Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 73-73 ◽  
Author(s):  
Michele Cavo ◽  
Francesca Patriarca ◽  
Paola Tacchetti ◽  
Monica Galli ◽  
Giulia Perrone ◽  
...  
Keyword(s):  
Partial Response ◽  
Induction Therapy ◽  
Autologous Transplantation ◽  
Phase Iii ◽  
Primary Study ◽  
Control Group ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
To Receive

Abstract In May 2006, the Italian Myeloma Network GIMEMA initiated a multicenter, randomized phase III study comparing VTD (arm A) with TD (arm B) incorporated into ASCT for newly diagnosed MM. Both VTD and TD were planned to be administered before (induction) and after (consolidation) double ASCT with melphalan 200 mg/m2 (MEL-200). In both arms, induction therapy consisted of three 21-d courses [63 days (d)]. The VTD regimen included Vel, 1.3 mg/m2 on d 1, 4, 8, and 11, plus Dex, 40 mg on each day of and after Vel administration; Thal was given at 200 mg/d from d 1 to 63. Patients randomized to TD received Thal as in arm A and Dex 40 mg/d on d 1–4 and 9–12 of every 21-d cycle. Primary study end point was complete response [either immunofixation negative (CR) or immunofixation positive (nCR)] to induction therapy. Secondary study end points included CR+nCR to consolidation therapy, time to progression, event-free survival, overall survival and toxicity. An interim analysis was planned to be performed after one year from study initiation to assess efficacy and toxicity of induction therapy. As of May 30, 2007, 234 patients entered the study and 187 were evaluated for response to induction therapy and adverse events (AEs). Of these patients, 92 were randomly assigned to receive VTD and 95 to receive TD. Efficacy and toxicity analyses were performed on an intention-to-treat basis. The rate of CR+nCR to VTD was 38% vs 7% to TD (P<0.001); 60% of patients in VTD arm and 25% of patients in the control group attained at least a very good partial response (P<0.001). Patients who failed at least a partial response to VTD were significantly less than those who failed on TD (7% vs 21%, respectively; P=0.004). Grade ≥ 2 and grade ≥ 3 AEs were similar in both arms, with the exception of grade ≥ 3 skin rash (6.5% in VTD arm vs 1% in TD arm; P=0.04). Grade 3 peripheral neuropathy was reported in 8% of patients randomly assigned to VTD and in 2% of patients treated with TD (P=0.07). All patients received acyclovir prophylaxis against reactivation of varicella zoster virus (VZV). VZV infection occurred in 2% of patients in VTD arm and in 1% of patients in the control group. Treatment discontinuation due to AEs was required in a single patient in each of the two treatment arms. No patient died for any cause during the induction phase. In a subgroup of patients with longer follow-up response to first ASCT was also evaluated. The rate of CR or CR+nCR to MEL-200 was significantly higher in VTD arm than in the control group (P=0.02 for CR comparison and P=0.05 for CR+nCR comparison between the two treatment arms). Preliminary analysis of this study provides demonstration that VTD is a highly active and well tolerated induction regimen, resulting in a significantly higher CR or CR+nCR rate compared to TD both before ASCT and after the first autologous transplantation with MEL-200.

A Phase III PETHEMA/GEM Study of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma: Superiority of VTD (Bortezomib/Thalidomide/Dexamethasone) Over TD and VBMCP/VBAD Plus Bortezomib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 307-307 ◽  
Author(s):  
Laura Rosiñol ◽  
María Teresa Cibeira ◽  
Maria Victoria Mateos ◽  
Joaquin Martinez ◽  
Albert Oriol ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Research Funding ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Advisory Committees ◽  
Intention To Treat ◽  
Grade 3

Abstract Abstract 307 Introduction: In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200. Primary end points: response rate after induction and after ASCT and time to progression. Patients and Method: TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. Four patients failed the eligibility criteria. 386 patients (median age: 56 yrs; M: 207, F: 179; IgG: 233, IgA: 85, light chain: 57, IgD: 9, Ig M: 2) were analyzed. The stage according to the ISS was I in 147 patients, II in 160, III in 75 and unknown in 4 and 66 patients (17%) had extramedullary soft-tissue plasmacytomas (EMP). Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics (t(4;14), t(14;16), and/or 17p deletion). One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Prognostic factors, including cytogenetics, were similar in the 3 arms. Response, survival and toxicity were evaluated on an intention-to-treat basis. Responses reported by investigators were centrally reassessed. Result: The IFE negative CR rate was significantly higher with VTD (35%) compared to TD (14%) and VBMCP/VBAD/B (22%) (p=0.0001 and p=0.01, respectively). The progressive disease (PD) rate during induction was significantly lower with VTD than with TD (7% vs. 23%, p=0.001). In patiens with high-risk cytogenetics, the CR rate was significantly greater with VTD when compared with TD (35% vs. 0%, p=0.002) and with VBMCP/VBAD/B (35% vs. 22%, p=0.02). The CR rate to VTD in patients with 17p deletion was 58% while none of the patients with this cytogenetic abnormality responded to TD or to VBMVP/VBAD/B (p=0.03 and p=0.02, respectively). Of interest, the CR rate in patients with t(11;14) was significantly lower than in patients lacking this abnormality (11% vs. 27%, p=0.01). This low CR rate in patients with t(11;14) was similar in the 3 arms. In the overall series, PD was significantly higher in patients with EMP (24% vs. 11%, p=0.01) with a significantly higher PD rate for TD as compared to VTD (40% vs. 12%, p=0.02). The incidence of thrombotic events was 2%, 6% and 5% for VTD, TD and VBMCP/VBAD/B, respectively (p=NS). The frequency of grade ≥ 3 peripheral neuropathy was 12% with VTD compared to 1% in both the TD and the VBMCP/VBAD/B arms (p= 0.0002). Treatment was discontinued due to toxicity en 16 patients (VTD:9, TD:4, VBMCP/VBAD/B:3). Nine patients died during the induction period (3 in each arm). On an intention to treat basis, the post-ASCT CR rate was higher in the VTD arm compared with TD (46% vs. 24%, p=0.004) and VBMCP/VBAD/B (46% vs. 38%, p=0.1). The estimated overall survival (OS) at 4 years was 76% with no significant differences among the 3 arms. After a median follow-up of 27 months, the progression-free survival (PFS) was not reached with VTD while it was 27 and 38 months with TD and VBMCP/VBAD/B, respectively (p=0.006). In the overall series, patients with high-risk cytogenetics had a significantly shorter OS (p=0.00007) and PFS (p=0.004). In addition, when compared with the good-risk group, patients with high-risk cytogenetics showed a trend towards a shorter PFS either after induction with VTD (median not reached vs. 17 months, p=0.05) and with TD (median 28 vs. 15 months, p=0.09). Conclusion: Induction with VTD resulted in a significantly higher CR rate in both the overall series and in patients with high-risk cytogenetics. The post-ASCT CR rate was also significantly higher with VTD than with TD and there was a trend when compared with VBMCP/VBAD/B. Finally, VTD resulted in a significantly longer PFS. However, longer follow-up is required to establish whether or not VTD will overcome the poor prognosis of patients with high-risk cytogenetics. Disclosures: Rosiñol: Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Bortezomib and Thalidomide are not approve for first line in Spain. Cibeira:Janssen-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. De La Rubia:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Blade:Janssen-Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Randomized phase III study of adjuvant versus progression-triggered treatment with gemcitabine (G) after radical cystectomy (RC) for locally advanced bladder cancer (LABC) in patients not suitable for cisplatin-based chemotherapy (CBC) (AUO-trial AB22/00).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 250-250 ◽  
Author(s):  
Jan Lehmann ◽  
Michael Kuehn ◽  
Claus Fischer ◽  
Bjoern Volkmer ◽  
Friedrich von Rundstedt ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Intention To Treat ◽  
Kaplan Meier ◽  
Node Positive Disease ◽  
Secondary Endpoints ◽  
The Difference ◽  
Grade 3

250 Background: Cisplatin-based chemotherapy (CBC) has been widely used in trials of adjuvant therapy for LABC after RC. A high proportion of patients are unfit for CBC after RC for LABC. We therefore performed a prospective randomized phase III trial on G-monotherapy administered as adjuvant therapy (G-adj) vs in case of progression (G-prog) in pts not suitable for CBC. Methods: Between 7/2000 and 12/2008 120 of 178 planned pts with LABC unfit for CBC were randomized between 6 adjuvant cycles of G (q3w) starting within 12 wks after RC and G in case of disease progression. The primary endpoint of the trial was progression-free survival (PFS). Secondary endpoints included cancer-specific (CSS) and overall survival (OS) as well as treatment related toxicity. Results: The trial of 178 planned pts was closed early due to slow accrual. Of 120 randomized pts from 29 centers 114 were eligible for analysis. Median age of 81 male and 33 female pts was 72 (45-82) years. Lymph-node positive disease was found in 52/114 (47%) of pts at the time of surgery. The intention-to-treat analysis demonstrated a 10% difference in PFS after 3 years 50% (G-adj) vs 40% (G-prog) with a median PFS of 23 mo (G-adj) vs 17 mo (G-prog). The difference in PFS was not statistically significant (nss) (p= 0.335; HR 1.375, 95%CI 0.719 - 2.627). CSS at 3ys: 56% (G-adj) vs 50% (G-prog) with a median CSS of 49 mo (G-adj) vs 38 mo (G-prog). The difference in CSS was nss (p= 0.622; HR 1.166, 95%CI 0.632 - 2.149). OS at 3ys: 49% (G-adj) vs 48% (G-prog) with a median OS of 32 mo (G-adj) vs 31 mo (G-prog). The difference in OS was nss (p= 0.426; HR 1.225, 95%CI 0.743 - 2.018). Treatment with G was usually well tolerated, with less than 15% grade 3/4 toxicities..There was one treatment related death in the G-adj arm. Conclusions: The study-hypothesis of a 15% difference in PFS after 3 years in favor of G-adj vs G-prog could not be confirmed. Nevertheless a marked difference in survival in favor of G-adj was shown by Kaplan-Meier plots regarding PFS, CSS and OS within the first 24 months after RC. Clinical trial information: NCT00146276.

Comparison of l and dl forms of folinic acid in Gercor C96.1 trial (A phase III trial comparing bimonthly LV5FU2 to monthly high-dose 5FU-leucovorin in patients with Dukes’ B2 and C colon cancer)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15004-e15004
Author(s):  
E. M. Quinaux ◽  
I. Baumgaertner ◽  
A. Khalil ◽  
C. Louvet ◽  
M. E. Buyse ◽  
...  
Keyword(s):  
Overall Survival ◽  
Folinic Acid ◽  
Statistical Significance ◽  
Disease Free Survival ◽  
Hazard Ratio ◽  
Phase Iii ◽  
High Dose ◽  
The Difference ◽  
Grade 3

e15004 In C96.1 study (André T et al; J Clin Oncol. 2007 20;25:3732–8), patients were randomized to either monthly 5FU-LV hd (dl LV 200 mg/m2 or l LV 100 mg/m2 15 min iv followed by 5FU 400 mg/m2 15 min iv, d1–5 q4 wk) or LV5FU2 (dl LV 200 mg/m2 or l LV 100 mg/m2 2-hour infusion followed by iv bolus 5FU 400 mg/m2 and 22 hours continuous infusion 600 mg/m2, d1 and d2 q 2 wk). Form l LV was administered to 60% (n=519) of patients and dl LV to 40% (n=357) of patients. It was unknown in 29 patients. No randomization was made between form l or dl (It was the choice of each center). The aim of this analysis was to compare the 2 LV forms in term of safety and efficacy. Important prognostic characteristics were well balanced between the 2 groups. The proportion of any grade III-IV toxicity was 20% in l form and 17% in dl form. There was no difference in term of toxicity between the two groups, except a trend for more diarrhea grade 3–4 in form l (8% in l form vs 4% in dl form, p=0.07). The median follow-up time was 6.2 years in l form and 6.0 years in dl form. There were no statistically significant differences between l and dl forms in term of disease free survival (33.3% vs 32.8% of patients with at least one event in l and dl forms respectively, hazard ratio=1.03, 95% CI=[0.82–1.31], p=0.78). In term of overall survival, there was a trend without statistical significance in favor of l form (21.8% vs 25.5% of patients who died, hazard ratio=1.28, 95% CI=[0.97–1.69], p=0.078). We conclude that the toxicity profile is similar between the two forms (excepted diarrhea). The difference in overall survival should not be attributed to folinic acid form as no difference was observed on DFS. No significant financial relationships to disclose.

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