Combined Treatment with Lenalidomide (LEN) and Epoetin Alfa (EA) Is Superior to Lenalidomide Alone in Patients with Erythropoietin (Epo)-Refractory, Lower Risk (LR) Non-Deletion 5q [Del(5q)] Myelodysplastic Syndrome (MDS): Results of the E2905 Intergroup Study-an ECOG-ACRIN Cancer Research Group Study, Grant CA180820, and the National Cancer Institute of the National Institutes of Health

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 223-223 ◽  
Author(s):  
Alan F List ◽  
Zhuoxin Sun ◽  
Amit Verma ◽  
John M. Bennett ◽  
Kathy L McGraw ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Combined Treatment ◽  
Phase Iii ◽  
Advisory Committees ◽  
Median Response ◽  
Erythroid Response ◽  
Receptor Complexes ◽  
Erythroid Precursors

Abstract Background: Treatment with rhu-Epo ameliorates anemia in a subset of LR-MDS patients, however, effective salvage therapy is limited. LEN promotes erythroid lineage competence and expansion of primitive erythroid precursors in vitro. In the MDS-002 and MDS-005 trials, treatment with LEN improved erythropoiesis, yielding RBC transfusion-independence in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. We previously reported that LEN restores Epo-responsiveness in MDS progenitors by inducing formation of lipid rafts enriched for signaling competent JAK2/Epo-receptor complexes and excluding large isoforms of the JAK2/lyn kinase-phosphatase CD45 (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In a pilot study of Epo-refractory MDS patients, addition of EA yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome resistance and augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 (Int-1) risk IPSS MDS with hemoglobin <9.5 g/dL who were unresponsive to rhEpo treatment or were TD (>2 units/mo) with serum Epo >500mU/mL were eligible for study. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). Primary endpoint was IWG 2006 major erythroid response (MER) rate after 4 cycles. Arm A non-responders were offered cross-over to combined therapy. Secondary endpoints included analysis of response biomarkers. Results: Between April 2009 and May 2016, 248 patients were enrolled and 195 were randomized and will be included in the primary analysis. Interim analysis of 163 patients (Arm A, 81; B, 82) accrued before July 2015 showed that the study met predefined stopping criteria. Baseline characteristics were balanced between arms. Median age was 74 years (range, 47-89) receiving a median of 2 RBC units/mo (0-8). Overall, 64 (39%) patients had Low IPSS risk and 90 (55%) Int-1 risk. Among these, 150 received prior rhuEpo (92%) and 27, azanucleosides (17%). In an ITT analysis, MER rate was significantly higher with combination therapy, Arm B 25.6% (n=21) vs. Arm A 9.9% (n=8) (P=0.015). Among 116 patients evaluable at week 16, 33.3% (20/60) and 14.3% (8/56) achieved MER, respectively (P=0.018), with a median response duration of 25.4 months vs. not reached in Arm A responders. Response to combined treatment was associated with baseline CD45-isoform distribution in erythroid precursors. Patients achieving MER had a significantly lower CD45 RA+RB:RO ratio (median, 1.51) compared to non-responders (median, 4.21; P=0.04), favoring homo-dimerization of the short CD45-RO isoform and inhibition of phosphatase activity. MER rate in Arm B patients with a low isoform ratio (< median) was 72.7% vs. 18.2% in the high ratio group (P=0.03). Thirty-four Arm A non-responders crossed over to combination-therapy with only 1 MER. There was no difference in the frequency or distribution of >Grade 3, non-hematologic AEs. Conclusions: LEN restores sensitivity to rhEpo in Epo-refractory LR-non-del(5q) MDS patients to yield durable and significantly higher rates of erythroid response to combination treatment without added toxicity. Erythroid CD45 isoform profile may serve as a response biomarker for selection of candidates for combination therapy. Disclosures Bennett: Celgne: Membership on an entity's Board of Directors or advisory committees. Altman:Syros: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Schiffer:Teva: Other: DSMB member; BMS: Research Funding; Ariad: Research Funding; Pfizer: Other: DSMB member.

scholarly journals 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 ◽  
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 &gt;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 &gt;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 &gt;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&lt;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.

Prognostic Importance of Duration of MDS Prior to Randomization Between Decitabine (DAC) Vs. Best Supportive Care (BSC) In Elderly IPSS Intermediate-2 and High Risk MDS Patients: Results of the 06011 EORTC-GMDSSG Phase III Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4024-4024
Author(s):  
Michael Lubbert ◽  
Stefan Suciu ◽  
Uwe Platzbecker ◽  
Aristoteles A.N. Giagounidis ◽  
Dominik Selleslag ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
Response Predictors ◽  
Long Duration

Abstract Abstract 4024 Background: The hypomethylating agents 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, DAC) are active in different MDS subtypes. Compared to other response predictors to DAC, prior MDS duration has received only limited attention (1, 2), with conflicting results. Based on our finding that long duration of MDS prior to DAC treatment may be a novel factor linked to a better outcome (1), we now assess its value in the phase III trial 06011 (DAC versus BSC [3]). Immediate enrolment after diagnosis was allowed in that trial, median MDS duration prior to randomization thus only 3 months (mths). Methods: Comparison of progression-free (PFS), AML-free (AMLFS) and overall survival (OS) according to MDS duration >= vs. <3 mths in 233 patients (pts) with higher-risk MDS (median age 70 years) randomized to DAC (n=119) or BSC (n=114). Comparisons by long-rank test and multivariate analyses by Cox regression (Performance Status [PS], cytogenetics and IPSS high risk N/Y) were performed retrospectively: MDS duration had not yet been known as possible stratification factor at time of study initiation, and the trial thus not been powered to detect significant differences with regard to this discriminator. Results: A better prognosis of patients with MDS duration >=3 vs <3 mths was observed in DAC arm (B vs A) and BSC arm (D vs C). Conversely, DAC yielded better results than BSC in each MDS duration group: <3 mths (A vs C) and >=3 mths (B vs D). In both arms (n=233), Mult. indicated that MDS duration (>=3 vs <3 mths) adjusted for treatment, PS, cytogenetics and IPSS group was an independent prognostic factor regarding PFS (HR=0.75, 95%CI 0.58–0.99), AMLFS (HR=0.68, 95%CI 0.51–0.90), and OS (HR=0.75, 95%CI 0.56–0.99). The tests for interaction treatment × duration of MDS were not significant for 3 endpoints: PFS (p=0.38), AMLFS (p=0.90), OS (p=0.67). Conclusion: In intermediate-2 and high-risk MDS pts, long duration from MDS diagnosis to start of DAC or BSC appeared to be associated with a better outcome. This finding is in sharp contrast to the adverse prognostic impact of antecedent disease duration in patients who received intensive chemotherapy (4). It is supported by a similar analysis of pts with AML from MDS treated on the 00331 DAC phase II multicenter trial: those with longer MDS duration prior to DAC also had better outcome (5). Application of this discriminator in the evaluation also of other DAC schedules and MDS treatments therefore appears warranted. References: 1. Wijermans et al., Ann. Hematol. 84 (suppl. 1): 9–14, 2005 2. Kantarjian et al., Cancer 109:265-73, 2007 3. Wijermans et al., Blood 112 (suppl. 1): abs. 226, 2008 4. Estey et al., Blood 90:2969-77, 1997 5. Lübbert, Schmoor et al., abstract submitted, ASH 2010 Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salih:Pfizer: Research Funding. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 763-763 ◽  
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.

Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1992-1992 ◽  
Author(s):  
Eugen Tausch ◽  
Christina Galler ◽  
Richard Schlenk ◽  
Peter Hillmen ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Gene Mutations ◽  
Phase Iii ◽  
Response To Treatment ◽  
Prognostic Impact ◽  
Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Efficacy, Safety, and Confirmation of the Recommended Phase 2 Dose of Ruxolitinib Plus Panobinostat in Patients with Intermediate or High-Risk Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 711-711 ◽  
Author(s):  
Jean-Jacques Kiladjian ◽  
Florian H Heidel ◽  
Alessandro M. Vannucchi ◽  
Vincent Ribrag ◽  
Francesco Passamonti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Spleen Volume ◽  
Bone Marrow Fibrosis ◽  
Advisory Committees ◽  
Expansion Phase ◽  
Marrow Fibrosis

Abstract Background: Myelofibrosis (MF) is a clonal neoplastic disease resulting in bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. The Janus kinase (JAK) pathway is often dysregulated in MF, and agents targeting this pathway have demonstrated efficacy in this disease. Ruxolitinib (RUX), a potent JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume reduction, symptom improvement, and survival compared with the control arm in the phase III COMFORT-I and COMFORT-II studies. Panobinostat (PAN), a potent pan-deacetylase inhibitor (pan-DACi), inhibits JAK signaling through disruption of the interaction of JAK2 with the protein chaperone heat shock protein 90. In phase I/II studies, PAN has shown splenomegaly reduction and improvement of bone marrow fibrosis. The combination of RUX and PAN demonstrated synergistic anti-MF activity in preclinical studies. These preliminary results led to the initiation of a phase Ib study evaluating the combination of RUX and PAN in patients (pts) with MF. The updated results from the expansion phase of this trial are presented here. Methods: Eligible pts had intermediate-1, -2, or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF by International Prognostic Scoring System criteria, with palpable splenomegaly (≥ 5 cm below the costal margin). The primary objective was determination of the maximum tolerated dose (MTD) and/or recommended phase II dose (RPIID). Secondary objectives included safety, efficacy, and pharmacokinetics. Exploratory endpoints included assessment of improvement in bone marrow fibrosis and reduction of JAK2 V617F allele burden. The treatment schedule was RUX (5-15 mg) twice daily (bid) every day and PAN (10-25 mg) once daily 3 times per week (tiw; days 2, 4, and 6) every other week (qow) in a 28-day cycle. Following dose escalation and identification of the potential RPIID, additional pts were enrolled into the expansion phase and treated at this dose. Results: As of March 14, 2014, a total of 61 pts were enrolled (38 escalation phase and 23 expansion phase). The median duration of exposure to PAN and to RUX was 24.6 weeks and 24.0 weeks, respectively, for pts treated in the expansion phase. Three DLTs were observed in the escalation phase (grade 4 thrombocytopenia [n = 2], grade 3 nausea [n = 1]). No MTD was reached. The RPIID was confirmed to be RUX 15 mg bid and PAN 25 mg tiw qow in May 2014. Among the 34 pts treated at the RPIID, grade 3/4 adverse events (AEs) regardless of causality included anemia (32%), thrombocytopenia (24%), diarrhea (12%), asthenia (9%), and fatigue (9%). AEs led to discontinuation in 6% of pts treated at the RPIID. Two pts treated at the RPIID died due to causes unrelated to study treatment (1 due to myocardial infarction and 1 due to progression of myelofibrosis). Among the pts treated at the RPIID, 79% showed a >50% decrease in palpable spleen length, with 100% decrease (non-palpable spleen) being observed in 53% of pts. Additionally, 48% of pts treated at the RPIID in the expansion phase achieved ≥35% reduction in spleen volume (Figure). These results are similar to those observed for spleen volume response at 24 weeks among pts who received single-agent RUX on the phase III COMFORT-I (41.9%) and COMFORT-II (32%) studies. Conclusions: The combination of the JAK1/JAK2 inhibitor RUX and the pan-DACi PAN was well tolerated and resulted in high rates of reductions in splenomegaly in pts with intermediate- and high-risk MF. Although a relatively larger proportion of patients experienced spleen volume reductions at week 24 as compared to the COMFORT studies, the smaller sample size, shorter follow up times and potential differences in the patient populations preclude definitive comparisons. Similar to COMFORT-I and II trials, hematological AEs, specifically anemia and thrombocytopenia, were the most common AEs observed in pts treated with the combination therapy. Pts continue to be treated in the expansion phase at the RPIID. Updated safety, efficacy, and exploratory analyses on bone marrow fibrosis, JAK V617F allele burden, and biomarkers, including cytokines, will be presented. Figure Change in Spleen Volume in Expansion Phase Figure. Change in Spleen Volume in Expansion Phase Disclosures Kiladjian: Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Honoraria, Research Funding. Heidel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ribrag:Celgene: Consultancy; Pharmamar: Consultancy; Epizyme: Research Funding; Bayer: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding. Conneally:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kindler:Novartis: Consultancy. Acharyya:Novartis: Employment. Gopalakrishna:Novartis: Employment. Ide:Novartis: Employment, Equity Ownership. Loechner:Novartis: Employment. Mu:Novartis: Employment. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Honoraria; SBio: Consultancy; Shire: Speakers Bureau.

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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 189-189 ◽  
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.

A Phase-Ib/II Study of Ruxolitinib Plus Pomalidomide in Myelofibrosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 826-826 ◽  
Author(s):  
Frank Stegelmann ◽  
Markus Bangerter ◽  
Florian H Heidel ◽  
Martin Griesshammer ◽  
Holger Hebart ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Board Of Directors ◽  
Clinical Improvement ◽  
Research Funding ◽  
Severe Neutropenia ◽  
International Prognostic Scoring System ◽  
Advisory Committees ◽  
Phase Ib ◽  
Treatment Interruptions ◽  
Rbc Transfusion

Abstract Background: Myelofibrosis (MF) patients (pts) frequently suffer from constitutional symptoms, splenomegaly, and cytopenia. While ruxolitinib (RUX) is available for the treatment of symptomatic splenomegaly and constitutional symptoms in MF, therapeutic options for the treatment of cytopenia are limited. Recent data indicate that the immunomodulatory drug pomalidomide (POM) may improve anemia and thrombocytopenia in a subset of MF pts (e.g. Tefferi et al., J Clin Oncol 2009). We designed a single arm, multicenter phase-Ib/II combination study of RUX and POM (MPNSG-0212 trial, NCT01644110) to evaluate potential synergistic effects of both drugs in MF. Study Design: Primary endpoints are response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and achievement of red blood cell (RBC) transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, quality of life, progression-free survival, and overall survival. Main inclusion criterion is pre-treated or untreated primary or secondary (post-ET / post-PV) MF with anemia (Hb <10 g/dL and/or RBC transfusion dependency). Key exclusion criteria are suitability for allotransplant, low platelet count (<100 /nL), and severe neutropenia (ANC <0.5 /nL). While POM is given at the fixed dosage of 0.5 mg QD, RUX is started at 10 mg BID with dose modifications being allowed to optimize efficacy and to manage myelosuppression. According to a Simon´s two-stage design, recruitment will be extended to a total number of 72 pts if response is achieved in a minimum of 12/37 pts tested initially. Results: Safety of the combination therapy was evaluated favorably by an independent safety monitoring committee after treatment of the first 6 pts as reported previously (Stegelmann et al, ASH 2014). Here, we present follow-up data from 25 pts. Median age of the study population was 75 years (range 51-82). Ten of 25 pts (40%) had one or more previous therapies. The most frequent previous drugs were hydroxyurea (n=6), ruxolitinib (n=3), EPO (n=2), pomalidomide (n=2), and steroids (n=2). Median Hb at study entry was 8.6 g/dL (range 6.8-10.6); 6 pts (24%) were RBC transfusion dependent. Median spleen size measured by ultrasound was 18 cm (range 13-28). Eight pts (32%) were intermediate-1, 10 pts (40%) intermediate-2, and 7 pts (28%) high-risk according to the dynamic international prognostic scoring system (DIPSS). Mutation frequencies of JAK2 V617F, MPL W515L, and CALR exon 9 were 72%, 12%, and 16%, respectively. ASXL1 was mutated in 5 pts (20%). Regarding safety, 287 adverse events (AE) of any grade (CTCAE 1-5) were recorded. Among these, worsening of anemia (°3/°4) was the most frequent AE (n=35 in 9 pts), followed by musculoskeletal pain (n=25 in 6 pts; °1-°3), and constitutional symptoms (n=13 in 2 pts; °1-°3). In total, 11 serious AE (SAE) CTCAE °2-5 were recorded. While 9 SAE (pneumonia °3, n=3; cardiac decompensation °5, malignant melanoma °2, septic shock °5, syncope °3, and TIA °2, worsening of general condition °3, n=1 each) were considered non-related to the study drugs, 2 SAE (hemoglobin °4, neuropathy °3) were considered related. Of note, neuropathy resolved after end of study. Treatment interruptions and dose reductions of RUX were uncommon. RUX could be step-wise increased to 15 or 20 mg BID in 10 pts (40%). Median time on treatment was 8 28-days cycles (range 1-13) in 24 pts, while one patient has not yet started therapy; 14 pts (56%) are still on study treatment. A total of 10 pts (40%) discontinued, due to death (n=2), no response after 12 cycles (n=5), or withdrawal of informed consent (n=3). Within this short observation time, 3 pts experienced ´clinical improvement´ (CI) according to IWG-MRT criteria in the following categories: i) spleen reduction, ii) spleen reduction + increase of Hb, and iii) increase of both Hb and ANC. RBC transfusion independency criteria have not yet been fulfilled in transfusion dependent pts. None of the study pts progressed during treatment. Conclusions: Taking into account that the majority of study pts were pre-treated and at advanced risk, the combination therapy of RUX and POM was well tolerated and is feasible. First efficacy evaluation shows that clinical improvement regarding reduction of splenomegaly and improvement of cytopenia is achieved in a subset of MF pts. Recruitment of the study continues. An update on safety and efficacy will be presented at the meeting. Disclosures Hochhaus: ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schlenk:Arog: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Analysis of Outcomes of Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated in Randomized Clinical Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4000-4000 ◽  
Author(s):  
Raffi Tchekmedyian ◽  
Paul Elson ◽  
Aaron T. Gerds ◽  
Navneet Majhail ◽  
Hetty E. Carraway ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Phase Iii ◽  
Advisory Committees ◽  
The Past ◽  
American Society ◽  
Over Time

Abstract Introduction The major reasons for failure to achieve cure in the majority of AML patients (pts) are primary refractoriness of disease to initial chemotherapy or failure to maintain complete remission (CR) that has been achieved (relapse). There is no uniformly accepted standard treatment for relapsed or refractory (RR) AML, with most available therapies regarded as palliative or as a bridge to allogeneic transplantation. While the past two decades have witnessed trials of several investigational therapies in RR AML, data regarding the effectiveness of these interventions remains unclear. We studied the impact of experimental drugs in RR AML pts by undertaking a comprehensive analysis of all phase 2 and 3 randomized clinical trials (RCTs) reported in the past 3 decades. Methods We searched PubMed, Embase, Cochrane Controlled Trials Register electronic databases, ClinicalTrials.gov and conference abstracts from the American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) websites covering a period from 1988 to 2015. Key words used during this search included "refractory" or "relapsed" or "AML" or "phase II" or "phase III" or "randomized". Only double-arm, phase II with a sample size of at least 50 pts and phase III RCTs conducted in RR AML pts were included. Two reviewers independently extracted data on study methods, participants, therapies, and outcomes from all eligible trials: differences in how to classify agents in RCTs were resolved by discussion. The primary outcomes examined in the experimental arms (EAs) and standard arms (SAs) included CR rates, disease-free survival (DFS), refractory disease rates, treatment-related mortality (TRM) rates and overall survival (OS). Odds ratios (OR) were used to summarize differences between EAs and SAs. The DerSimonian and Laird random-effects model was used to compare them and to assess the overall impact of time. Results Of 5500 included pts, 40.5% were treated on 21 double-arm, phase II trials, 51% on 10 phase III trials and 6.6% analyzed through 4 retrospective studies. There was no change in CR rates in either EAs (p=.21) or SAs (p=.15) over time (Figure 1). The CR rates in EAs tended to be higher than in SAs [OR=1.24; 95% CI, 1.02-1.50, p=.03). Rates of disease refractoriness to salvage regimens in both EAs (p=.70) and CAs (p=.31) did not change over time and these rates were not significantly different between treatment arms [OR=0.82; 95% CI, 0.62-1.08, p=.16]. TRM rates tended to decrease over time but the change was not significant in either group [p=.24 for SAs and p=.33 for EAs]. TRM rates were higher in SAs compared to CAs but did not reach statistical significance [OR=1.21; 95% CI, 0.97-1.50, p=.09]. Over time, there was no significant change inDFS in either group (p=.32 for CAs and p=.58 for EAs). DFS rates did not differ between EAs and SAs [OR=1.01; 95% CI, 0.86-1.19, p=.89] (Figure 2). OS tended to remain stable over time in both groups [p=.85 for SAs and p=.66 for EAs]. While OS tended to be higher in SAs, it did not reach statistical significance [OR=0.93; 95% CI, 0.83-1.05, p=.27]. Conclusions: These findings indicate a lack of significant or clinically meaningful improvement in disease outcomes, including OS, in RR AML pts treated within RCTs over the past 3 decades. Greater efforts need to be directed towards designing RCTs using novel statistical approaches and directed agents based on recent discoveries of targetable mutations. Disclosures Carraway: Amgen: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Celgene Corporation: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Advani:Pfizer Inc.: Consultancy, Research Funding; Blinatumomab: Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

First Analysis of an International Double-Blind Randomized Phase III Study of Lenalidomide Maintenance in Elderly Patients with DLBCL Treated with R-CHOP in First Line, the Remarc Study from Lysa

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 471-471 ◽  
Author(s):  
Catherine Thieblemont ◽  
Hervé Tilly ◽  
Maria Gomez da Silva ◽  
Rene-Olivier Casasnovas ◽  
Christophe Fruchart ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
First Line ◽  
Advisory Committees ◽  
Double Blind

Abstract Background. R-CHOP is the standard first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). However 30% of patients will relapse and 70% of relapsed patients will die within 2 years of diagnosis. The REMARC study (clinicalTrials.gov NCT01122472) is an international, multicenter, double-blind, randomized, placebo controlled, phase III trial that assessed the benefit of lenalidomide (LEN) maintenance after response to R-CHOP in patients aged 60 to 80 years with untreated DLBCL, FL3b or transformed lymphoma. Patients achieving CR or PR at the end of 6 or 8 cycles of R-CHOP21 or R-CHOP14 were stratified by CR/PR status and country and randomized 1:1 to receive 2 years of LEN maintenance (25 mg/day for 21 of every 28 days) or placebo (PBO). The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints were safety, PR to CR conversion rate, and overall survival (OS). Diagnosis was retrospectively centrally reviewed. In patients with adequate samples, GCB/nonGCB profile was assessed by the Hans algorithm and GCB/ABC/unclassified profile was assessed using NanoString gene expression profiling technology. Methods. From 05/2009 to 05/2014, 784 patients were enrolled either before R-CHOP (n= 437) or after completion of 6 or 8 cycles of R-CHOP (n= 347). At the end of R-CHOP therapy, 650 patients were randomized to maintenance, either in CR (n= 495) or in PR (n= 152). Central review found that 3 patients were randomized in SD or PD, all in LEN arm. At time of diagnosis, median age was 68 y (range 58-80), 43.5% were older than 70 y, and 56% were male. aaIPI was low in 38.5% and high in 57.5% of patients (missing data 4%). COO analyses are ongoing for both Hans algorithm and NanoString technology. Results. With a median follow-up of 40 months, median PFS (according to independent centralized radiology review) was not reached in the LEN group versus 68 months in the PBO group (hazard ratio favoring the LEN group, 0.708 (95% CI 0.537-0.932; p=0.0135))(See Figure). In the LEN group, 18 patients (21%) converted from PR to CR during maintenance compared to 13 patients (14%) in the PBO group. Immature overall survival data did not show any benefit for LEN arm, a lack of difference not attributable to an excess of lymphoma relapse, secondary cancer or safety problems in LEN arm. Deaths generally occurred off study drug (median time from last dose of study drug to death was 277 days (range 20, 1291) in LEN arm and 334 (41, 1594) in control arm. During maintenance, the most common observed grade 3 or 4 AEs were neutropenia (56% vs. 22%), rash (5% vs. 1%), infections (8% vs. 6%), and thrombocytopenia (2.5% vs. 0.6%) in LEN and PBO arms, respectively. Dose adjustments were necessary in 72% of the LEN patients and 42% of PBO patients. 59% of patients stopped LEN and 40% stopped PBO for toxicity (p<0.001). Median number of cycles was 15 in LEN and 25 in PBO (p<0.001). Secondary primary malignancies occurred in 33 patients receiving LEN and in 42 patients on PBO. Conclusion. This analysis of the REMARC study shows that 2 years of LEN maintenance in patients responding to R-CHOP significantly improved PFS (primary endpoint) without an early significant impact on OS. The COO analysis is currently ongoing. This is the first report finding that using an immunomodulatory agent as maintenance therapy prolongs PFS for patients with DLBCL after first line treatment with R-CHOP. Figure 1. Progression-free survival of elderly patients with diffuse large B-cell lymphoma in response to R-CHOP treated in maintenance with either lenalidomide or placebo Figure 1 Figure 1. Disclosures Thieblemont: Celgene: 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; Roche: Research Funding; Bayer healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gomez da Silva:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; ROche: Consultancy, Membership on an entity's Board of Directors or advisory committees; takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Haioun:Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Celgene: 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. Cabecadas:celgene: Consultancy, Honoraria. Salles:Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Coiffier:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: 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.

Comparison of Autologous Hematopoietic Cell Transplant (autoHCT), Bortezomib, Lenalidomide (Len) and Dexamethasone (RVD) Consolidation with Len Maintenance (ACM), Tandem Autohct with Len Maintenance (TAM) and Autohct with Len Maintenance (AM) for up-Front Treatment of Patients with Multiple Myeloma (MM): Primary Results from the Randomized Phase III Trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 - StaMINA Trial)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. LBA-1-LBA-1 ◽  
Author(s):  
Edward A Stadtmauer ◽  
Marcelo C. Pasquini ◽  
Beth Blackwell ◽  
Kristin Knust ◽  
Asad Bashey ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Disease Risk ◽  
Phase Iii ◽  
Second Primary ◽  
Cell Transplant ◽  
Second Primary Malignancy ◽  
Primary Malignancy ◽  
Advisory Committees

Abstract Background: Len maintenance after autoHCT has improved progression-free (PFS) and overall survival (OS). However, the role of additional interventions after autoHCT such as tandem autoHCT or triple therapy consolidation remains to be determined. Methods: This is a phase III clinical trial (NCT#01109004) of transplant-eligible patients (pts) with symptomatic MM <71 years of age within 12 months of initiating therapy and without prior progression who were randomly assigned 1:1:1 to receive melphalan 200mg/m2 autoHCT and 4 cycles of RVD consolidation (lenalidomide 15mg daily days 1-14, dexamethasone 40mg day 1,8 and 15, and bortezomib 1.3mg/m2 days 1,4,8 and 11 every 21 days) (ACM), versus tandem melphalan 200mg/m2 autoHCT (TAM) or versus a single autoHCT (AM). Randomization was stratified by disease risk (cytogenetic abnormalities - del13q by karyotype, del17q, t(4;14), t(14;16), t(14;20) and hypodyploid; or high beta-2 microglobulin) and center. All arms included Len maintenance (at maximum tolerated dose of 5 to 15 mg orally daily until progression) with dose modifications for toxicities. All patients were reviewed centrally for eligibility, response and progression. The primary objective was to compare 38-month PFS of the three arms. The events for PFS included progression, non-protocol anti-myeloma therapy, or death. Comparisons between treatment groups were based on pairwise log-rank tests stratified on disease risk, with significance levels adjusted for the 3 pairwise comparisons and for interim analyses. In calculating the cumulative incidence of progression, the events were progression or non-protocol anti-myeloma therapy, and death was a competing risk. Results: From June 2010 to November 2013, 758 pts (ACM, N=254; TAM, N=247; AM, N=257) aged 20-70 years (median 57y) were enrolled. Of those enrolled, 24% were classified as high risk. Non-compliance rates following the first autoHCT were 12%, 32% and 5% for ACM, TAM and AM, respectively. Median available follow up from randomization was 38 months. Follow-up is continuing through January 2017. 38-month estimated probabilities for PFS were 57% (95% CI: 50-63%), 56% (95% CI: 49-63%) and 52% (95% CI: 45-59%) for ACM, TAM and AM, respectively (ACM vs TAM p=0.75, ACM vs AM p=0.21, TAM vs AM p=0.37). Corresponding probabilities of OS were 86% (95% CI: 80-90%), 82% (95%CI: 76-87%) and 83% (95% CI: 78-88%). Median OS has not been reached. Cumulative incidences of disease progression at 38 months were 42% (95% CI: 36-48%), 42% (95% CI: 35-48%) and 47% (95% CI: 40-54%) for the ACM, TAM and AM arms, respectively. There were 39 cases of second primary malignancy (SPM) reported in 36 participants and the cumulative incidences for first SPM were 6.0% (95% CI: 3.4-9.6%), 5.9% (95% CI: 3.3-9.6%) and 4.0% (95% CI: 1.9-7.2%) for the ACM, TAM, and AM, respectively. Conclusions: The primary results of the largest randomized US transplant trial in MM demonstrated comparable PFS and OS. The addition of RVD consolidation or a second auto-HCT was not superior to a single auto HCT followed by Len maintenance in the upfront treatment of MM. A long term follow-up trial to track outcomes in these patients is ongoing. Disclosures Stadtmauer: Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy. Pasquini:Atara: Other: travel reimbursement for a meeting; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees. Efebera:Millennium/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria. Ganguly:Onyx: Speakers Bureau; Seattle Genetics: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Giralt:Celgene: Consultancy; Millenium/Takeda: Consultancy. Hari:Celgene: Consultancy; Millennium/Takeda: Consultancy. McCarthy:Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Millennium/Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; The Binding Site: Consultancy, Honoraria. Qazilbash:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Membership on an entity's Board of Directors or advisory committees. Vesole:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Vij:Millennium/Takeda: Consultancy; Celgene: Consultancy. Vogl:Celgene: Consultancy; Millennium/Takeda: Consultancy, Research Funding. Somlo:PUMA: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Speakers Bureau; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Krishnan:Celgene: Consultancy, Speakers Bureau; Millennium/Takeda: Consultancy, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document