Results of the Primary Analysis of Complement A+B: A Phase III Study of Ofatumumab in Combination with Bendamustine Versus Bendamustine Alone in Patients with Indolent Non-Hodgkin's Lymphoma That Is Unresponsive Following Rituximab or Rituximab-Containing Regimen

Abstract Background: Despite a variety of treatment options, indolent non-Hodgkin's lymphoma (iNHL) remains a largely incurable disease with patients experiencing multiple relapses. Both rituximab (RTX) and bendamustine (Benda) are used as single agents for the treatment of relapsed/refractory iNHL. When given in combination to patients with relapsed iNHL, high response rates were observed (Rummel, 2016). Ofatumumab (OFA) is a human, anti-CD20 type-I antibody that binds a distinct epitope from RTX. A phase I/II study showed that OFA has activity in patients with follicular lymphoma (FL) who relapsed after RTX-containing therapy (Hagenbeek, 2008). Based on these experiences, COMPLEMENT A+B evaluated if OFA+Benda would improve progression-free survival (PFS) compared to Benda alone in unresponsive or progressive iNHL after RTX or RTX-containing regimen. Methods: This phase III, open-label, randomized, global, multi-center study enrolled adult patients (≥18 years) with CD20+ small lymphocytic, marginal zone, lymphophasmacytic and Grades 1-3A FL who had either stable disease after or disease progression during or within 6 months of RTX or RTX-containing regimen. Patients were randomized (1:1) to receive either OFA+Benda or Benda. Benda (90 mg/m2 in OFA+Benda arm and 120 mg/m2 in Bendaarm) was given on Days 1 and 2 every 21 days for up to 8 cycles. OFA (1000 mg) was given on Day 1 of Benda cycles and then every 28 days for a total of 12 doses. The primary endpoint was PFS as assessed by an independent review committee (IRC). Key secondary endpoints included PFS in patients with FL, overall response rates (ORR) and overall survival (OS) in all patients and in patients with FL which were tested hierarchically if the prior endpoint was statistically significant. Results: Overall, 346 patients were enrolled (173 in each arm) in 85 centers across 15 countries. Baseline characteristics were similar between the 2 arms. Median (range) age was 62 (21-87) years, majority were males (59%) and 69% had FL. Ann Arbor Stage IVA was common (OFA+Benda: 43%; Benda: 42%). Median duration of follow up was 61.1 months. Median treatment duration was longer in the OFA+Benda arm (OFA+Benda: 260 days; Benda: 135 days). Median (range) number of prior RTX therapy was 1 (1-8). In the OFA+Benda arm, 58% and 65% completed treatment with OFA and Benda, respectively, whereas in the Benda arm, 43% completed treatment. The main reason for premature discontinuation of OFA treatment in OFA+Benda arm was adverse events (AEs), 14%. The main reason for premature treatment discontinuation of Benda was AEs (OFA+Benda: 17%; Benda: 27%). Primary analysis was performed after 217 IRC-assessed PFS events occurred. In the OFA+Benda and Benda arms, 61% and 65% of patients, respectively, had PFS events (Figure 1). Median IRC-assessed PFS was 16.7 months in the OFA+Benda arm and 13.8 months in the Benda arm (hazard ratio [HR]=0.82, 95% confidence interval [CI] [0.62, 1.07]; p=0.1390). Similar results were seen in patients with FL where the median IRC-assessed PFS was similar in FL patients - 16.6 months in the OFA+Benda arm and 12.1 months in the Benda arm (HR=0.76, 95% CI [0.55,1.06]; p=0.1076) (Figure 2). IRC-assessed ORR was similar in both arms (OFA+Benda: 73%; Benda: 75%; difference in ORR [95% C]: -1.2% [-10.4%, 8.1]; p=0.8003). Median OS was 58.2 months and 51.8 months in the OFA+Benda and Benda arms, respectively (HR=0.89, 95% CI [0.63, 1.25]; p=0.4968). Frequencies of deaths (OFA+Benda: 38%; Benda: 41%) and on-treatment deaths (OFA+Benda: 7%; Benda: 9%) were similar in both arms. The main cause of death during the study was disease under study (OFA+Benda: 20%; Benda: 15%). Overall, 73% of patients in the OFA+Benda arm and 80% in the Benda arm experienced a ≥ Grade 3 AE. The most common ≥ Grade 3 AEs were neutropenia, thrombocytopenia, anemia, and leukopenia (Table 1). Conclusions: No significant improvement in PFS was seen with OFA+Benda as compared with Benda alone for patients with RTX-refractory iNHL. The safety profile for OFA was consistent with prior experience. The difference in outcomes compared to those in the GADOLIN trial (Sehn, 2016) could be due to the differences in drug exposure as patients in the GADOLIN study received maintenance anti-CD 20 therapy for up to 2 years; in the patient population as approximately 80% had FL in GADOLIN versus 69% in COMPLEMENT A+B; and in the mechanism of action of type-1 versus type-2 monoclonal antibody. Disclosures Rummel: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Eisai: Honoraria. Janssens:Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. MacDonald:Roche Canada: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Merck: Honoraria. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davis:Novartis: Employment. Lasher:Novartis: Employment. Lobe:Novartis: Employment. Izquierdo:Novartis: Employment, Equity Ownership. Friedberg:Bayer: Honoraria.

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Differences in Quality of Life Between Bendamustine Plus Rituximab Compared with Standard First-Line Treatments in Patients with Previously Untreated Advanced Indolent Non-Hodgkin's Lymphoma or Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.155.155 ◽

2012 ◽

Vol 120 (21) ◽

pp. 155-155 ◽

Cited By ~ 2

Author(s):

John M. Burke ◽

Richard H. Van der Jagt ◽

Brad S. Kahl ◽

Peter Wood ◽

Tim E. Hawkins ◽

...

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Final Visit ◽

Advisory Committees ◽

Non Hodgkin's Lymphoma ◽

Pharmaceutical Industries

Abstract Abstract 155 Background Bendamustine is a unique alkylating agent, active as monotherapy and in combination with rituximab for relapsed and refractory indolent non-Hodgkin's lymphoma (NHL). This study compared efficacy and safety of bendamustine-rituximab (BR) with standard treatment regimens of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in first-line treatment of patients with indolent NHL or mantle cell lymphoma (MCL). The primary objective was to determine whether the complete response rate for BR was noninferior to R-CHOP/R-CVP (presented separately). The present analysis reports results for quality of life (QOL) as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). Methods Previously untreated patients with indolent NHL or MCL were randomized to receive BR (bendamustine 90 mg/m2/day on days 1 and 2; rituximab 375 mg/m2 on day 1 of each 28-day cycle) or R-CHOP/R-CVP (rituximab 375 mg/m2 and vincristine 1.4 mg/m2 (up to maximum 2 mg) on day 1 and prednisone at 100 mg on days 1–5 (of a 21-day cycle), plus either [1] cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 or [2] cyclophosphamide 750 mg/m2 or 1000 mg/m2(investigator choice) on day 1. QLQ-C30 was administered at screening (baseline); after cycles 1, 3, 6, 8; and at the end-of-treatment visit. Linear transformation to standardize raw scores was performed. The QLQ-C30 is composed of 5 multi-item functional scales, 1 global health status (GHS)/QOL scale, 3 symptom scales, and 6 single-item measures; all scores could range from 0 to 100. Rising scores for functional scales and GHS/QOL indicate improvement. Rising scores for symptom scales/single items indicate worsening. GHS/QOL score change at last QLQ-C30 administration postbaseline was interpreted using analysis of covariance. Data from the last observation (end-of-treatment visit) were analyzed. Results The 447 enrolled patients were randomly assigned to 1 of the 2 treatments; 224 to BR (NHL n=187, MCL n=36, missing n=1) and 223 to R-CHOP/R-CVP (NHL n=184, MCL n=38, missing n=1). Treatment groups were well matched for demographic and clinical characteristics. Among all randomized patients, mean change in GHS/QOL score from baseline to final visit was significantly higher (indicating relative improvement) for patients treated with BR than those treated with R-CHOP/R-CVP (3.6 vs −5.1 respectively, P=0.0005). For patients with indolent NHL, mean change in GHS/QOL score by final visit was significantly higher in patients treated with BR than those receiving R-CHOP/R-CVP (2.1 vs −6.3, respectively, P=0.0021); in patients with MCL, mean change in GHS/QOL score was numerically higher in the BR group, but the difference was not statistically significant (10.9 vs 1.6, P=0.0654). All randomized patients receiving BR showed greater improvement in QLQ-C30 Emotional Functioning (from baseline to final visit), compared with patients receiving R-CHOP/R-CVP. Mean change from baseline scores (± SEM) for QLQ-C30 for Cognitive, Physical, Role, and Social Functioning scales of the QLQ-C30 decreased (signifying deteriorating effect) in both treatment groups, with patients treated with BR deteriorating less than patients treated with R-CHOP/R-CVP (Figure). For symptom scales/item measures, patients treated with BR showed larger reductions in mean scores from elevated baseline levels (signifying greater improvement), compared with R-CHOP/R-CVP for Appetite Loss (−2.9 for BR vs −1.1 for R-CHOP/R-CVP), Pain (−5.6 vs −1.7), and Constipation (−0.7 vs 1.8). For symptom scales/item measures of Dyspnea, Fatigue, and Financial Difficulties, both treatments showed deteriorating effects, with BR showing less than R-CHOP/R-CVP: Dyspnea (0.8 vs 4.8), Fatigue (0.5 vs 7.2), and Financial Difficulties (0.9 vs 1.3). Patients receiving R-CHOP/R-CVP had larger reductions in mean scores for Insomnia (−2.1 for BR vs −6.7 for R-CHOP/R-CVP), Diarrhea (0.5 vs −1.3), and Nausea and Vomiting (1.8 vs 0.9). Conclusions In this study, BR significantly improved GHS/QOL, compared with R-CHOP/R-CVP treatment, in previously untreated patients with indolent NHL or MCL. In addition, BR provided improved patient QOL scores for most aspects of functioning and symptoms, as measured by the QLQ-C30. Support: Teva Pharmaceutical Industries Ltd. Disclosures: Burke: Spectrum Pharmaceuticals: Consultancy. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Van der Jagt:Celgene: Consultancy, Research Funding, Sponsorship Other; Novartis: Consultancy, Research Funding, Sponsorship, Sponsorship Other; Roche: Consultancy, Sponsorship, Sponsorship Other; Teva: Consultancy, Research Funding; Incyte: Research Funding; Xanthus: Research Funding; Bristol-Myers Squibb: Consultancy. Kahl:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. MacDonald:Lundbeck: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Teva Pharmaceutical Industries Ltd.: Employment. Munteanu:Teva Pharmaceutical Industries Ltd.: Employment. Clementi:Teva Pharmaceutical Industries Ltd.: Employment. Chen:Teva Pharmaceutical Industries Ltd.: Employment. Flinn:Teva: Research Funding.

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R-CHOP, Followed by High Dose Therapy and Autologous Stem Cell Rescue (HDT/ASCR), and R-Hypercvad Have Equivalent Progression-Free Survival and Are Superior to R-CHOP Alone in Younger Patients with Mantle Cell Lymphoma: a Comparative Effectiveness Analysis From the National Comprehensive Cancer Network (NCCN) Non-Hodgkin's Lymphoma Outcomes Database Project.

Blood ◽

10.1182/blood.v114.22.403.403 ◽

2009 ◽

Vol 114 (22) ◽

pp. 403-403 ◽

Cited By ~ 8

Author(s):

Ann LaCasce ◽

Jonathan L. Vandergrift ◽

Maria A. Rodriguez ◽

Allison L. Crosby ◽

Eva M. Lepisto ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

Hodgkin's Lymphoma ◽

Advisory Committees ◽

Non Hodgkin's Lymphoma ◽

Mantle Cell

Abstract Abstract 403 Background: Mantle Cell Lymphoma (MCL) is an uncommon histology of non-Hodgkin's lymphoma (NHL) with an unfavorable prognosis for which optimal initial therapy has not been clearly defined. Despite a number of single center studies and uncontrolled trials examining first-line therapy options in MCL, no randomized clinical trials or observational studies have directly compared initial therapeutic options in a single cohort of patients. The role of aggressive induction therapy versus sequential standard chemotherapy remains uncertain, particularly in younger patients. We therefore used the NCCN NHL Outcomes Database to compare R-HyperCVAD, R-CHOP followed by HDT/ASCR and R-CHOP alone as first-line therapy. Our endpoints were progression-free survival (PFS) and overall survival (OS). Methods: The NCCN Non-Hodgkin's Lymphoma Outcomes Database is a prospective cohort study collecting comprehensive clinical, treatment, and outcome data for patients seen at 7 participating NCCN centers. Overall, 229 patients <65 years old with newly diagnosed MCL presented at NCCN institutions between August 2000 and February 2009. Patients were excluded if they (1) were enrolled in clinical trial (n=27), (2) did not receive Rituximab therapy (n=27), (3) did not receive either R-HyperCVAD or R-CHOP induction therapy (n=10), or (4) received both R-CHOP and R-HyperCVAD as induction (n=9). Induction therapy was determined as the initial chemo-immunotherapy received within 180 days of diagnosis. HDT/ASCR consolidation was defined as a transplant after achieving remission. In the R-CHOP+ HDT/ASCR group, ASCR was initiated within 100 days of induction therapy for 90% of patients. The maximum time from induction to ASCR was 172 days. In total, 156 patients were included in the final analysis. Median follow-up was 30 months. Results: Overall, 28 (18%) patients received R-CHOP alone, 29 (19%) received R-CHOP+HDT/ASCR, and 99 (63%) received R-HyperCVAD. No significant differences were observed between therapy groups with regards to co-morbidity (p=0.419), ECOG performance status (p=0.216), B symptoms (p=0.685), bulky disease (p=0.647), IPI risk group (p=0.247), or bone marrow involvement (p=0.651). No difference in PFS (p=0.546) was observed between the R-HyperCVAD and R-CHOP+HDT/ASCR arm (figure 1a). R-CHOP without consolidation had significantly poorer PFS than both R-HyperCVAD (p=0.001) and R-CHOP+HDT/ASCR (p=0.001). No significant differences in OS were observed between the three groups. However, there was a strong trend favoring R-HyperCVAD over R-CHOP (p=0.082, figure 1b). Conclusion: R-CHOP was inferior to both R-HyperCVAD and R-CHOP+HDT/ASCR, which had equal PFS and OS in patients with de novo mantle cell lymphoma. Even with these aggressive induction regimens in younger patient populations, the median PFS in these cohorts was only 3 years. Future trials should focus on incorporating novel agents rather than comparing efficacy of current suboptimal regimens. Disclosures: Czuczman: NCCN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nademanee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blayney:American Society of Clinical Oncology: Membership on an entity's Board of Directors or advisory committees; BlueCross Blue Shield of Michigan: Research Funding; NCCN: Honoraria; University of Michigan Health System: Employment. Friedberg:Genentech: Membership on an entity's Board of Directors or advisory committees.

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Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽

10.1182/blood.v130.suppl_1.901.901 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 901-901

Author(s):

Sara Bringhen ◽

Massimo Offidani ◽

Pellegrino Musto ◽

Anna Marina Liberati ◽

Giulia Benevolo ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Cell Transplant ◽

Newly Diagnosed ◽

Community Based ◽

Advisory Committees ◽

Risk Of Death ◽

Grade 3 ◽

To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p<0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

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A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v122.21.763.763 ◽

2013 ◽

Vol 122 (21) ◽

pp. 763-763 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Francesca Gay ◽

Andrew Spencer ◽

Francesco Di Raimondo ◽

Adam Zdenek ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Study Endpoint ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Quadruplet Vs Sequential Triplet Induction Therapy Approaches to Maximise Response for Newly Diagnosed, Transplant Eligible, Myeloma Patients

Blood ◽

10.1182/blood.v126.23.189.189 ◽

2015 ◽

Vol 126 (23) ◽

pp. 189-189 ◽

Cited By ~ 3

Author(s):

Charlotte Pawlyn ◽

Faith E Davies ◽

David A Cairns ◽

Corinne Collett ◽

Anna Chalmers ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Initial Response ◽

Response Rates ◽

Phase Iii ◽

Induction Treatment ◽

Cell Transplant ◽

Medical Sciences ◽

Advisory Committees ◽

Sequential Strategy

Abstract Background: Maximising response in myeloma (MM) patients with effective induction regimens prior to autologous stem cell transplant (ASCT) improves progression-free and overall survival. Triplet regimens combining an immunomodulatory agent (IMiD) and/or proteasome inhibitor (PI) are standard of care, however a more personalised approach is achieved by sequential triplet combinations based on an individual's response. Alternatively, quadruplet regimens may be more effective and new generation PIs such as carfilzomib, with less off-target activity, provide the opportunity to investigate this whilst minimising the risk of increased toxicity. The UK NCRI Myeloma XI trial is a large, phase III study aiming to answer these questions in transplant eligible (TE) patients comparing the quadruplet carfilzomib, cyclophosphamide, lenalidomide and dexamethasone to the sequential strategy of triplet IMiD combinations (with thalidomide or lenalidomide) followed by additional PI triplet therapy for those with a suboptimal response (<VGPR) prior to ASCT. Methods: In 2013, the TE pathway was amended to include KCRD: carfilzomib 36mg/m2 IV d1-2,8-9,15-16 (20mg/m2 #1d1-2), cyclophosphamide (cyclo) 500mg PO d1,8, lenalidomide (len) 25mg PO d1-21, dexamethasone (dex) 40mg PO d1-4,8-9,15-16). Patients are randomised to this up-front quadruplet or the sequential strategy of CRD: cyclo 500mg PO d1,8, len 25mg PO d1-21 PO daily, dex 40mg PO d1-4, 12-15 or CTD: cyclo 500mg PO d1,8,15 thalidomide 100-200mg PO daily, dex 40mg PO d1-4,12-15 given to max. response - patients with VGPR/CR proceed straight to ASCT, PR/MR are randomised to sequential CVD: cyclo 500mg d1,8,15, bortezomib 1.3mg/m2 IV/SC d1,4,8,11, dex 20mg PO d1,2,4,5,8,9,11,12 or nothing and SD/PD all receive sequential CVD. All treatments are given to max. response prior to ASCT, after which there is a maintenance randomisation. Patients: 1512 patients entered the TE pathway prior to amendment (756 CRD, 756 CTD). Of these, 201 patients with a suboptimal initial response went on to receive CVD, 142 following randomisation (initial response PR/MR) and 59 with NC/PD. 788 (of target n=1036) patients have been randomised post-amendment to date (394 KCRD, 197 CRD, 197 CTD). Results: TE patients receiving treatment prior to the amendment had response rates ≥VGPR: CRD 58% vs CTD 52%. For patients receiving the sequential triplet CVD due to a suboptimal response this was upgraded to ≥VGPR in 49% of those with initial MR/PR, 27% with NC/PD. This suggests the overall ≥VGPR rate to this treatment approach prior to ASCT would be approx. 75%. This now needs to be compared to the alternative approach of an upfront quadruplet. Comparing patients contemporaneously randomised to initial induction the patients receiving KCRD have completed a median 4 cycles (range 1-7), CRD 5 (range 1-10) and CTD 6 (range 1-9). Dose modifications have been required in 62% of patients receiving KCRD (56% to carfilzomib, 42% to lenalidomide) 44% CRD (40% to lenalidomide) and 65% CTD (59% to thalidomide). Data for study drug related toxicity in patients who have completed at least one cycle of initial induction are shown in table 1. Serious adverse events suspected to be due to trial medications have occurred in 37% on KCRD, 32% CRD and 35% CTD. Updated toxicity and preliminary response analysis on 23/09/15 will be presented at the meeting. This will include a response comparison at the end of initial induction regimen i.e. KCRD vs CRD vs CTD for an anticipated 700 contemporaneous patients who will have completed treatment. Updated response to the sequencing approach (with 250 patients having received sequential CVD) will also be presented and compared. Conclusions: In our study KCRD, an outpatient delivered 4-drug regimen combining second generation IMiD and PI drugs, is well-tolerated in TE NDMM patients, comparable to 3-drug regimens. Data will be presented at the meeting to compare the response rates achieved with the different regimens and treatment approaches. On behalf of the NCRI Haemato-oncology CSG Table 1. Comparative toxicities KCRD n=261 CRD n=143 CTD n=142 % (no. of patients) Peripheral neuropathy Sensory Gr II-IV 1.9 (5) 1.4 (2) 8.5 (12) Motor Gr II-IV 3.1 (8) 1 (1) 5.6 (8) VTE all grades 4.2 (11) 4.9 (7) 5.6 (8) Anaemia Gr III-IV 9.2 (24) 4.2 (6) 5.6 (8) Neutropenia Gr III-IV 14.9 (39) 16.1 (22) 13.3 (19) Thrombocytopenia Gr III-IV 8.4 (22) 1.4 (2) 1.4 (2) Infusion reaction Gr III-IV 0.4 (1) - - Disclosures Pawlyn: Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Off Label Use: Carfilzomib as induction treatment for myeloma Lenalidomide and vorinostat as maintenance treatments for myeloma. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Honoraria; Onyx-Amgen: Honoraria; Takeda-Milenium: Honoraria. Jones:Celgene: Other: Travel support, Research Funding. Kaiser:Janssen: Honoraria; Chugai: Consultancy; Amgen: Consultancy, Honoraria; BristolMyerSquibb: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Jenner:Takeda: Honoraria; Amgen: Honoraria. Cook:Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Russell:Therakos: Other: shares. Owen:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Gregory:Janssen: Honoraria; Celgene: Honoraria. Jackson:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Morgan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; CancerNet: Honoraria; Weisman Institute: Honoraria; MMRF: Honoraria; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Weisman Institute: Honoraria; CancerNet: Honoraria.

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Phase IIa Study of Single-Agent MOR208 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v126.23.1528.1528 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1528-1528 ◽

Cited By ~ 4

Author(s):

Wojciech Jurczak ◽

Pier Luigi Zinzani ◽

Gianluca Gaidano ◽

Andre Goy ◽

Mariano Provencio ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Hodgkin's Lymphoma ◽

Clinical Activity ◽

Advisory Committees ◽

Cd20 Antibody ◽

Grade 3

Abstract Introduction: There remains a high unmet medical need for new therapies for patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is a B-lymphocyte, lineage-specific surface antigen that is highly expressed by most B-cell NHLs. CD19 expression is maintained on lymphoma cells which have CD20 expression downregulated following treatment with the CD20 antibody, rituximab. Consequently, MOR208 (XmAb5574; MOR00208), an Fc-engineered, humanized, monoclonal antibody that targets CD19, may have clinical utility as a new therapeutic approach to R-R NHL. A phase I study showed MOR208 to be safe and well-tolerated with encouraging single-agent activity in patients with chronic lymphocytic leukemia (CLL); an intravenous dose of 12 mg/kg was recommended for phase II studies. Methods: This is a non-randomized, open-label, multicenter, two-stage, phase IIa study of MOR208 in adult patients with R-R NHL whose disease had progressed after at least one prior therapy containing the CD20 antibody, rituximab. In stage 1, 10 patients were to be enrolled into each of four NHL subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent NHL (iNHL) and mantle cell lymphoma (MCL). Patients were to receive single-agent MOR208, 12 mg/kg intravenously, weekly, for 8 weeks (2 cycles). Those with at least stable disease by the 2007 International Response Criteria could continue MOR208 treatment for an additional 4 weeks (total of 12 weeks of therapy). Patients with a complete or partial response (CR or PR) after 12 weeks could then receive MOR208 as maintenance therapy, every 2 or 4 weeks depending on the investigator's decision, until progression. In stage 2, cohorts with ≥2 responses (CR or PR) were to be expanded by at least 20 additional patients. The primary endpoint was the overall response rate (ORR). Key secondary endpoints included duration of response, safety, immunogenicity of MOR208, pharmacokinetics and pharmacodynamics. Results: The DLBCL and FL cohorts were expanded (to N=35 and N=34 patients, respectively), leading to a total enrollment of 92 patients: 56 (61%) were male; median age was 66.5 (range 35-90) years; 80 (87%) had stage III-IV disease; 41 (45%) had received ≥3 prior lines of therapy and 10 (11%) had received a prior stem-cell transplant. The investigator-assessed ORR across all NHL subtypes was 23% (21/92 patients; 16 not evaluable at cutoff) with clinical activity seen in the DLBCL (26% [9/35]; 2 CR, 7 PR); FL (26% [9/34]; 3 CR, 6 PR) and iNHL (27% [3/11]; 2 CR, 1 PR) cohorts (MCL, 0/12 responses). The iNHL cohort was not expanded as the response pattern in this subgroup was heterogeneous according to lymphoma subtype. The longest durations of response recorded to date are 15.4 months for FL and 14.2 months for DLBCL (both ongoing). Grade ≥3 non-hematologic and hematologic treatment-emergent adverse events (TEAEs) were recorded in 24 (26%) and 14 (15%) of 92 patients, respectively. The most commonly reported grade ≥3 hematologic TEAEs were neutropenia (7 [8%] of 92 patients, anemia (4 [4%]), and thrombocytopenia (4 [4%]); such TEAEs were seen most frequently in the DLBCL cohort (10 [29%] of 35 patients overall; neutropenia, 5 [14%], anemia, 4 [11%], thrombocytopenia, 2 [6%]). Dyspnea was the most commonly reported grade ≥3 non-hematologic TEAE (4 [4%] of 92 patients). Infusion-related reactions were seen in 9 (10%) of 92 patients; all were grade 1-2, except for one case of dyspnea, grade 4. There were no treatment-related deaths. Clinical activity in patients with R-R DLBCL appeared to be dependent on attaining a defined cumulative exposure (AUC0-t) over 8 weeks of around 11,000 day*µg/mL; i.e., at the data cutoff date, all 8 patients with a PR after 2 cycles showed an exposure above this potential threshold level. Conclusions: MOR208 demonstrated encouraging single-agent activity with CRs observed in patients with R-R DLBCL, FL, and iNHL. MOR208 was well tolerated without significant infusional toxicity. These data support further development of MOR208 in combination with other agents (including lenalidomide and bendamustine), and protocols for studies in patients with R-R DLBCL are now being developed. Disclosures Jurczak: CELLTRION, Inc,: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gaidano:Celgene: Research Funding; MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards. Goy:Celgene: Consultancy, Research Funding, Speakers Bureau; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Research Funding. Buske:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy. Korolkiewicz:MorphoSys AG: Employment. Striebel:MorphoSys AG: Employment. Blum:Morphosys: Research Funding; Gilead: Research Funding; Millenium: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene: Research Funding.

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A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients with AL Amyloidosis

Blood ◽

10.1182/blood.v128.22.646.646 ◽

2016 ◽

Vol 128 (22) ◽

pp. 646-646 ◽

Cited By ~ 27

Author(s):

Efstathios Kastritis ◽

Xavier Leleu ◽

Bertrand Arnulf ◽

Elena Zamagni ◽

María Teresa Cibeira ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Cardiac Response ◽

Phase Iii ◽

Al Amyloidosis ◽

Advisory Committees ◽

Phase Iii Trial ◽

Hematologic Response ◽

Grade 3

Abstract Background. Current upfront treatment of light chain (AL) amyloidosis is often based on bortezomib in patients. However, data on the safety and efficacy of bortezomib in this setting mostly derive from uncontrolled, retrospective series, that are difficult to compare due to different proportion of patients with advanced disease. Here we report the analysis of a multicenter randomized phase III trial comparing MDex, a current standard of care, and MDex with the addition of bortezomib (BMDex) in newly-diagnosed AL amyloidosis that was performed in Europe and Australia (EMN-03 study, NCT01277016). Patients and Methods. Main eligibility criteria included measurable disease (M-protein >10 g/L or dFLC >50 mg/L), estimated glomerular filtration rate (eGFR) ³30 mL/min, and adequate liver function. Previously treated patients, those who had >30% bone marrow plasma cell or lytic bone lesions, NYHA class >II heart failure, grade 3 sensory or grade 1 painful peripheral neuropathy, or ECOG performance status >2 were excluded. In January 2013 the protocol was amended to include Mayo stage III patients, provided their NT-proBNP was <8500 ng/L (stage IIIa). Patients were randomized to receive either MDex (melphalan at 0.22 mg/kg and dexamethasone at 40 mg daily for 4 consecutive days every 28 days) or BMDex (bortezomib added at 1.3 mg/m2, on days 1, 4, 8, and 11 in cycles 1 and 2, and on days 1, 8, 15, and 22 in the following cycles). The primary endpoint was overall hematologic response at 3 months. Treatment was continued until completion of MDex cycle 9 or BMDex cycle 8, or achievement of CR or of at least partial response (PR) plus organ response after cycle 6, and was discontinued in case PR was not achieved by cycle 3. Enrollment is now completed (110 patients) with the last patient enrolled in February 2016 (database lock: July 25, 2016). Results. Patients' characteristics are reported in the Table. The proportion of patients experiencing at least 1 grade 3-4 severe adverse events (SAE) was similar in the MDex and BMDex arms (49% vs. 60%, P=0.11). The total number of reported adverse events per cycle was lower in the MDex group (10% vs 23%, P<0.01). Most common SAEs (MDex vs. BMDex) were cytopenia (4% vs. 7%, P=0.04), fluid retention (3% vs. 6%, P=0.02), and neuropathy (0 vs. 2%, P<0.01). One patient died within 3 months in the MDex arm and 3 in the BMDex group (P=0.28). Response was evaluated by intent to treat. Hematologic response rates after cycle 3 were 51% and 78% (P=0.001), with 28% and 53% complete response (CR) /very good partial response (VGPR) (P=0.003), in the MDex and BMDex arms, respectively. Overall hematologic response at the end of treatment, after a median of 5 cycles, was 56% and 81% (P=0.001), with 38% and 64% CR/VGPR in the MDex and BMDex arms, respectively (P=0.002). Cardiac response was reached in 8 of 33 evaluable patients treated with MDex (24%) and 10 of 26 (38%) who received BMDex (P=0.119). Renal response was attained in 17 of 35 patients (48%) in both arms. However, there was a higher proportion of cardiac progression in the MDex arm with borderline statistical significance (32% vs. 15%, P=0.054). After a median follow-up of living patients of 25 months, 26 patients (24%) died, 16 in the MDex arm and 10 in the BMDex arm with no significant difference in survival (Figure 1a). Achievement of hematologic and cardiac response at 3 months significantly improved survival (Figures 1b and 1c). Conclusion. This is the first prospective randomized trial of novel agents in AL amyloidosis. The criteria of hematologic and cardiac response are validated in the prospective setting for the first time. The primary endpoint, hematologic response at 3 months has been reached, showing more frequent and more profound hematologic responses with BMDex, preventing progression of cardiac dysfunction, with a modest increase in toxicity. This regimen can be proposed as a new standard of care in AL amyloidosis. We would like to acknowledge the European Myeloma Network, the Australasian Leukaemia and Lymphoma Group and the Leukaemia Foundation of Australia for their ongoing support, and Janssen-Cilag for partially funding the trial and providing the study drug. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Nilelse: Research Funding. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Wechalekar:Takeda: Honoraria; Janssen: Honoraria; Glaxo Smith Kline: Honoraria; Celgene: Honoraria. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Merlini:Pfizer: Honoraria, Speakers Bureau; Millennium Takeda: Consultancy; Prothena: Honoraria; GlaxoSmithKline: Consultancy. Palladini:Prothena: Honoraria.

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Blinatumomab in Children with Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R-ALL): Final Results of 110 Patients Treated in an Expanded Access Study (RIALTO)

Blood ◽

10.1182/blood-2020-141336 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25

Author(s):

Franco Locatelli ◽

Gerhard Zugmaier ◽

Noemi Mergen ◽

Peter Bader ◽

Sima Jeha ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Final Analysis ◽

Publicly Traded ◽

Primary Analysis ◽

Advisory Committees ◽

Grade 3

Introduction: The open-label, expanded access study (RIALTO) demonstrated that blinatumomab is efficacious with a manageable safety profile in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates cytotoxic T cells to kill target B cells. Here, findings from the final analysis of RIALTO are presented (NCT02187354). Methods: Enrolled in the study were children >28 days and <18 years of age with R/R CD19+ BCP-ALL (defined as ≥2 relapses, relapse after allogeneic hematopoietic stem cell transplant [alloHSCT], or refractory to prior treatments) and ≥5% blasts or <5% blasts but with minimal residual disease (MRD) level ≥10−3. Blinatumomab was given as continuous infusion in a 6-week cycle (4 weeks on and 2 weeks off) for up to 5 cycles and safety follow-up visit 30 days post-treatment. Patients with <25% blasts were dosed at 15 µg/m2/day, whereas those with ≥25% blasts were dosed at 5 µg/m2/day (days 1-7 of cycle 1) followed by dose increase to 15 µg/m2/day. Primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included complete response (CR; <5% blasts) and MRD response (<10−4 blasts by PCR or flow-cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and alloHSCT rate after blinatumomab treatment. Results: As of the data cutoff date (January 10, 2020) for the final analysis, demographics and baseline characteristics of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 61% had <50% blasts at baseline, and 11% had <5% blasts (n=12; with MRD ≥10−3) remain unchanged compared with the primary analysis (Table 1). For best treatment response within the first 2 cycles, results are comparable to that of the primary analysis. Among 110 patients, overall CR rate was 62.7% (n= 69). Of 98 patients with ≥5% blasts at baseline, 59% (n=58) achieved CR; of them, 79% (n=46) achieved an MRD response and 62% (n=39) proceeded to HSCT. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response Among the 12 patients with <5% blasts but with MRD ≥10−3 at baseline, 92% (n=11) achieved CR and MRD response; 75% (n=9) proceeded to HSCT (Table 2). Of the 5 patients who had received prior blinatumomab , 4 achieved CR. Of 110 patients treated with blinatumomab, median OS (95% CI) was 14.6 (11-24.5) months with median follow-up time of 18.2 months, which increased by 1.5 months compared with that reported in the primary analysis, with 29.9% of patients still surviving at month 24. Median RFS (95% CI) remains unchanged at 8.5 months (4.7-14.0), with a median follow-up time of 11.5 months in patients who achieved CR; 38% of patients relapsed and 9% died. RFS was more favorable for patients who received HSCT post blinatumomab (70%) than for those who did not (30%) at month 12, respectively, which is consistent with the results from primary analysis. Among patients who had HSCT prior to blinatumomab (n= 45), median OS (95%) was 16.6 (7.1-NE) months vs 14.6 (10.9-24.5) months in patients without HSCT prior to blinatumomab (n= 65). Compared with the primary analysis, 5 additional patients received HSCT after achieving CR in the final analysis. Median OS among patients in CR after HSCT by MRD responders vs MRD non-responders was NE at 15-month analysis (Figure). Safety results in the final analysis were consistent with those reported in the primary analysis. Of 110 patients, 99% experienced TEAEs, with 65% being grade ≥3 (see Table 3 for details). TRAEs were reported in 74% of patients; 26% were grade ≥3 and 19% were deemed serious. Details on grade ≥3 TRAEs are shown in Table 3. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusions: Overall, the safety and efficacy results from the final analysis are consistent with those reported in the primary analysis as no new safety signals were observed. These findings strengthen the observation that blinatumomab demonstrates durable efficacy and is a suitable treatment option in children with R/R BCP-ALL. Table 1. Disclosures Locatelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceeutical: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Current Employment, Other: Personal Fees ; 20190300609: Patents & Royalties: Licensed patient . Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. Bader:Medac: Patents & Royalties, Research Funding; Amgen: Consultancy, Speakers Bureau; Neovii: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding. Schlegel:bluebird bio: Honoraria. Bourquin:Servier: Other: Travel Support. Handgretinger:Amgen: Honoraria. Brethon:Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Rössig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Viswagnachar:IQVIA: Current Employment.

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Bortezomib, Thalidomide, and Dexamethasone (VTD) Versus VTD Plus Cyclophosphamide as Induction Therapy in Previously Untreated Multiple Myeloma Patients Eligible for HDT-ASCT: A Randomized Phase 2 Trial.

Blood ◽

10.1182/blood.v114.22.2312.2312 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2312-2312 ◽

Cited By ~ 3

Author(s):

Heinz Ludwig ◽

Luisa Viterbo ◽

Richard Greil ◽

Tamas Masszi ◽

Ivan Spicka ◽

...

Keyword(s):

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Response Rates ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Phase 2 Study ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2312 Poster Board II-289 Bortezomib (Velcade®) has shown substantial activity and manageable toxicity in newly diagnosed multiple myeloma (MM) in combination with thalidomide (Thalomid®) and dexamethasone (VTD) in a phase 3 study (Cavo et al, ASH 2008), and with cyclophosphamide and dexamethasone (VCD) in a phase 2 study (Knop et al, ASCO 2009). Four-drug combinations may be more effective than 3-drug regimens, but may also be associated with increased toxicity. This randomized, non-comparative, open-label, multicenter, phase 2 study was designed to evaluate the efficacy and safety of VTD and VTD plus cyclophosphamide (VTDC) as induction therapy prior to high-dose therapy plus autologous stem cell transplant (HDT-ASCT). A total of 98 previously untreated MM patients with measurable disease who were candidates for HDT-ASCT were enrolled. Additional eligibility criteria included: age 18–70 years, Karnofsky Performance Status (KPS) ≥60%, adequate hematologic, hepatic, and renal function, and no grade ≥2 peripheral neuropathy (PN)/neuropathic pain. Patients were randomized (1:1), stratified by International Staging System (ISS) disease stage (I / II / III), to receive four 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, thalidomide 100 mg daily, and dexamethasone 40 mg on days 1–4 and 9–12 (VTD), or VTD plus cyclophosphamide 400 mg/m2 IV on days 1 and 8, as induction therapy prior to HDT-ASCT. All patients received antithrombotic prophylaxis. Patients who became ineligible for HDT-ASCT or had a complete response (CR) after induction therapy could receive an additional 4 cycles of treatment. Responses were categorized using modified IMWG Uniform Response Criteria (stringent CR [sCR] were unconfirmed by immunohistochemistry) through blinded review by the principal investigator and medical monitor, using central laboratory M-protein data and local bone marrow data. The primary efficacy endpoint was combined CR rate (sCR + CR + near-CR) following induction therapy. Secondary objectives included combined CR rate post-HDT-ASCT, overall response rate (ORR: ≥partial response) post-induction and post-HDT-ASCT, time to progression (TTP), overall survival (OS), and safety. Adverse events (AEs) were graded using NCI CTCAE v3.0. Forty nine patients were randomized to each arm; median age was 57 and 58 years in the VTD and VTDC arms, respectively, 53% and 51% of patients were male, 49% and 43% had KPS ≤80%, and 24 / 45 / 31% and 18 / 47 / 35% had ISS stage I / II / III MM. All but 7 patients completed induction; these patients discontinued due to AEs (3 [6%] each arm) and disease progression (1 [2%] VTDC). Four VTDC patients received additional cycles of treatment. One patient (VTDC arm) was not evaluable for response. Response rates following induction are shown in the table. Median CD34+ stem cell yields were 8.16 (VTD; n=48) and 8.13 (VTDC; n=40) x 106/kg. At data cut-off (April 10, 2009), 47 VTD and 35 VTDC patients had undergone HDT-ASCT; response rates post-HDT-ASCT in 38 and 27 evaluable patients are shown in the table. Time-to-event data are not mature (median follow-up: 9.8 months). The 1-year survival rate was estimated to be 94% in each arm. At least one AE was reported in 98% and 96% of patients on the VTD and VTDC arms, with at least one grade ≥3 AE reported in 47% and 59%, respectively. The most common non-hematologic grade 3/4 AEs included fatigue (2% and 8%) and constipation (6% and 2%); analyses of hematology laboratory values indicated grade 3/4 AEs of lymphopenia (39% and 77%), anemia (8% and 18%), neutropenia (14% and 18%), and thrombocytopenia (6% each). PN was reported in 35% (VTD) and 29% (VTDC) of patients, including 8% grade 3 in each arm and 2% grade 4 in the VTD arm. Two patients (1 [2%] each arm) had deep vein thrombosis; one (VTDC arm) was a grade 3 SAE. At least one serious AE (SAE) was reported in 22% (VTD) and 41% (VTDC) of patients, including 6% and 14% with SAEs of infections (MedDRA SOC), and 2% and 14% with musculoskeletal-related pain. In conclusion, both VTD and VTDC are highly active induction regimens, with CR rates and ORRs among the highest reported; the efficacy profiles were similar between the arms, but there were higher rates of toxicity in the VTDC arm compared with the VTD arm. Table. Response rates following induction and post-HDT-ASCT. Post-induction n=49 n=48 Combined CR*, % 51 44 sCR†, % 27 27 ORR, % 100 96 Post-HDT-ASCT n=38 n=27 Combined CR*, % 76 78 sCR, % 39 33 ORR, % 100 100 * sCR + CR + near-CR † unconfirmed Disclosures: Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Masszi:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen-Cilag: Honoraria. Dmoszynska:Milllennium: Research Funding. Cakana:Janssen Cilag: Employment, Equity Ownership. Enny:Johnson & Johnson: Employment, Equity Ownership. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership.

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High Dose Imatinib Induction Therapy (800 mg/day, 6 Months) In Pre-Treated Chronic Phase CML Patients Improves Cytogenetic and Molecular Responses but Does Not Improve Overall and Progression Free Survival – Final Results of the CELSG Phase III CML11 “ISTAHIT” Trial

Blood ◽

10.1182/blood.v116.21.2271.2271 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2271-2271

Author(s):

Andreas L Petzer ◽

Dominic Fong ◽

Thomas Lion ◽

Irina Dyagil ◽

Zvenyslava Masliak ◽

...

Keyword(s):

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

De Novo ◽

Chronic Phase ◽

Phase Iii ◽

High Dose ◽

Molecular Response ◽

Advisory Committees ◽

Grade 3

Abstract Abstract 2271 Introduction: Imatinib 400 mg/day represents the current standard treatment for de novo as well as pre-treated CML patients in chronic phase (CP). Recent randomized phase III trials revealed conflicting results concerning the potential higher efficacy of dose-increased imatinib in de novo treated CP-CML. Methods: We here present the final analyses including response data, OS, EFS and PFS of the multicenter, randomised, 2-arm phase III CELSG “ISTAHIT” trial evaluating imatinib high dose (HD) induction (800 mg/day, 6 months) followed by 400 mg/day as maintenance (experimental arm B) compared to continuous imatinib standard dose (400mg/day; arm A) in pre-treated CP CML patients. ClinicalTrials.gov Identifier: NCT0032726. Results: From a total of 243 patients screened for inclusion, 16 patients were not eligible (mainly due to non sufficient numbers of metaphases obtainable from the bone marrow before the start of the study). Of the remaining 227 patients, 113 patients were randomized into arm A and 114 patients into the experimental arm B. Subsequent data are presented as per protocol. No significant differences between treatment groups were observed regarding sex (55.5% female, 44.5% male), age (median: 46.3 years, range 18 –76), Sokal scores at diagnosis (30% low, 41% intermediate, 16% Sokal high risk, 13% unknown) and different pre-treatments, which included hydroxyurea (96%), interferon (72%), busulfan (17%) and “others” (26%; mainly Ara-C). The median observation time was 673 days. Cytogenetic responses were generally higher in the experimental arm B and revealed statistically significant differences in major cytogenetic responses (MCyR) at 3 and 6 months (month 3: 25.8% arm A, 48.3% arm B, p=0.002; month 6: 41.9% arm A, 58.8% arm B, p=0.029) as well as in complete cytogenetic responses (CCyR) not only during imatinib HD therapy (month 3: 7.5% arm A, 29.9% arm B, p<0.001; month 6: 20.4% arm A, 47.4% arm B, p<0.001) but also thereafter (month 12: 31.8% arm A, 52.9% arm B, p=0.006). The primary endpoint of the study, the achievement of an improved MCyR at 12 month was, however, not significantly different (56.8% arm A, 64.4% arm B). In line with improved cytogenetic responses, major molecular response (MMRIS) rates were also significantly better at 3, 6 and even at 24 months in the HD arm B (month 3: 3.7% arm A, 15.9% arm B, p=0.003; month 6: 9.4% arm A, 34.6% arm B, p<0.001; month 24: 26.5% arm A, 42.5% arm B, p=0.034). Surprisingly, however, this impressing improvement in cytogenetic and molecular remissions in patients achieving high dose imatinib as induction therapy did not translate into a better OS and PFS, both of which were comparable in the two treatment arms (OS: p=0.25; EFS: p=0.37). Moreover, the EFS was even significantly worsened in the experimental arm B (p=0.014). Grade 3/4 non-haematological toxicities during the first 6 months of therapy were comparable, whereas grade 3/4 haematological toxicities were significantly more common in the imatinib HD arm B. Conclusions: Although high dose imatinib induction induces more rapid and higher cytogenetic and molecular remission rates in pre-treated CP CML patients, OS as well as PFS were not improved and EFS was even worsened in the high dose induction arm B. Therefore we conclude that imatinib 400mg/day remains the standard of care for pre-treated CP-CML patients. Disclosures: Petzer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Imatinib 800mg is not licensed as the initial therapy of chronic phase CML. Lion: Novartis: Honoraria, Research Funding. Bogdanovic: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griskevicius: Novartis: Research Funding. Kwakkelstein: Celgene: Employment. Rancati: Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gastl: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wolf: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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