Efficacy of Front-Line Ibrutinib Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) in Patients with CLL. a Multicenter "Real-World" Study

Abstract Introduction: In previously untreated patients with chronic lymphocytic leukemia (CLL), treatment with ibrutinib plus rituximab improved progression-free survival (PFS) and overall survival (OS) compared to the standard fludarabine, cyclophosphamide and rituximab (FCR) chemoimmunotherapeutic regimen, based on the results of the phase III ECOG-E1912 trial. The improvement in PFS with ibrutinib plus rituximab was observed in patients with unmutated immunoglobulin heavy chain variable region gene (IGHV) but not in those with an IGHV mutated profile. However, the efficacy of ibrutinib compared to FCR has not yet been investigated in the real-world setting. Methods: A multi-center retrospective "real-world" study to compare the efficacy of front-line ibrutinib monotherapy versus standard FCR in patients with CLL. Demographic and clinical data of the FCR cohort were retrieved from the Israeli CLL Study Group database and of the ibrutinib from the Italian multicenter "Campus CLL" network and the CLL database of the department of hematology at the Sourasky Medical Center. Patients with a documented del(17p) or those who are participating in clinical trials were excluded. In order to fit both treatment samples, the maximum follow-up was censored at 48 months. IBM SPSS Statistics was used to analyze PFS and OS by Kaplan Meier Estimator, Log-Rank test and Cox Regression. In order to control for differences in patients' characteristics, the inverse probability of treatment weighting (IPTW) method with stabilized weights and truncation of 5% extreme score was applied by R. Results: A total of 235 patients who had been front-line treated with either FCR (n=136, 57.9%) or ibrutinib (n=99, 42.1%) were included (Table 1). Most patients were males (n=160, 68.1%), had an unmutated IGHV status (n=115, 70.6%) and were Binet stage B/C (n=191, 83.8%). By FISH, the most frequent abnormality was del(11q) (n=45, 23.1%) followed by trisomy12 (n=34, 17.4%) and del(13q) (n=43, 22.1%). Median time to first treatment was 29.4 months (IQR, 11.9-56.2), and it was not significantly different between ibrutinib (median=24.9 months, IQR 10.3-46.6) and FCR (median=34.0 months, IQR 13.8-60.1; p=0.101). Patients treated with FCR were younger than those treated with ibrutinib (median=58.4 years vs. 71.9 years; p<0.001). The median follow-up for the entire cohort was 48.0 months (37.2 months and 48 months for ibrutinib and FCR, respectively). PFS was longer with ibrutinib than with FCR, with a 3-year rate of PFS of 89.7% vs. 65.8%, respectively (HR=3.5, 95% CI [1.8-6.9], p<0.001) (Figure 1). By subgroup analysis, the PFS benefit with ibrutinib over FCR was maintained in the subgroups of patients age >65 years (n=100, 3-year PFS 89.4% vs. 53.1%; HR=3.9, 95% CI [1.6-9.9], p=0.002), Binet stage B/C (3-year PFS: 90.5% vs. 67.8%; HR=3.5, 95% CI [1.7-7.5], p<0.001) and unmutated IGHV (3-year PFS: 83.0% vs. 78.0%; HR=5.8, 95% CI [2.4-14.5], p<0.001). Among mutated IGHV patients the PFS was not significantly different between ibrutinib and FCR (3-year PFS: 83.0% vs. 78.0%; HR=1.2, 95% CI [0.3, 4.5]; P=0.795). In multivariate analysis (Table 2), only FCR was an independent predictor of decreased PFS (HR=5.1, 95% CI [1.8, 14.3], p=0.002). OS was also better with ibrutinib than with FCR, with a 3-year OS of 96.8% vs. 87.5%, respectively (HR=3.52, 95% CI [1.04-11.92], p=0.031) (Figure 2). Using IPTW, both PFS and OS were still superior with ibrutinib compared to FCR (HR=0.2, 95% CI 0.1-0.5, p<0.001 and HR=0.2, 95% CI [0.1-0.7], p=0.008, respectively). Conclusions: In a real-world setting, front-line treatment with ibrutinib improves PFS and OS in patients with CLL. Similar to the results of the phase III ECOG-E1912 trial, the improvement in PFS was preferentially observed in patients with unmutated IGHV. Figure 1 Figure 1. Disclosures Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Fineman: AbbVie: Research Funding. Mauro: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Tskeda: Consultancy, Honoraria. Reda: Abbvie: Consultancy; Astra Zeneca: Consultancy; Beigene: Consultancy; Janssen: Consultancy. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Laurenti: AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Shvidel: AbbVie: Honoraria, Research Funding. Coscia: Janssen: Honoraria, Other, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Other; AstraZeneca: Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Varettoni: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; beigene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees. Aviv: AbbVie: Honoraria, Research Funding. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Rossi: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Cellestia: Honoraria, Research Funding. Gaidano: Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cuneo: AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Gattei: abbVie: Research Funding; Janssen: Research Funding; Menarini: Research Funding.

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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 ◽

10.1182/blood.v124.21.1992.1992 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1992-1992 ◽

Cited By ~ 1

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.

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NOTCH1 Mutation and Treatment Outcome In CLL Patients Treated With Chlorambucil (Chl) Or Ofatumumab-Chl (O-Chl): Results From The Phase III Study Complement 1 (OMB110911)

Blood ◽

10.1182/blood.v122.21.527.527 ◽

2013 ◽

Vol 122 (21) ◽

pp. 527-527 ◽

Cited By ~ 7

Author(s):

Eugen Tausch ◽

Philipp Beck ◽

Richard F. Schlenk ◽

Sabrina Kless ◽

Christina Galler ◽

...

Keyword(s):

Prognostic Factors ◽

Board Of Directors ◽

Research Funding ◽

Mutant Allele ◽

Sanger Sequencing ◽

Phase Iii ◽

Advisory Committees ◽

Binet Stage ◽

Full Trial

Abstract Background Mutations in NOTCH1 (NOTCH1mut ) have been found in CLL with an incidence of about 10% and have been associated with unmutated IGHV, +12q, and poor outcome in previous studies. In the CLL8 trial (1st line FCR vs. FC), NOTCH1mut was identified as an independent unfavorable prognostic factor for progression free survival (PFS) and a predictive factor for reduced benefit from the addition of Rituximab to FC. Methods We assessed the incidence and impact of NOTCH1mut in the OMB110911 trial (1st line Chl vs. O-Chl) in patients considered inappropriate for fludarabine-based therapy. Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative for the full trial population. The mutation hotspot fragment (chr9:139,390,619-139,390,840) of exon 34 of NOTCH1 was analyzed by Sanger sequencing and by NGS using Illumina MiSeq. NGS was used to evaluate the sensitivity of Sanger sequencing to detect c.7541_7542delCT mutation and to determine the exact variant frequency of the mutant allele. Results The c.7541_7542delCT mutation was found by Sanger sequencing and by NGS in 45 (12.0%) of 376 patients (24 in O-Chl and 21 in Chl). When comparing baseline characteristics, there were significant associations of NOTCH1mut with +12q (p=0.01), absence of 13q- (p=0.006) and unmutated IGHV (p=0.009), but not with gender, age , Binet stage, ECOG, CIRS, B symptoms, WBC, ß2-MG, 6q-, 11q-, and 17p-. Regarding response to treatment, there was no association between NOTCH1mut and ORR or CR, neither in the whole group nor when analyzing the treatment arms separately. At a median follow-up of 29.0 months for PFS there were 249 events, at the medium follow-up of 31.7 months for OS 63 events in the 376 patient cohort. Similar to the full trial cohort, also in our cohort, O-Chl as compared to Chl resulted into significant improved PFS (median 22.4 vs. 13.1 months, HR=0.54, p<0.001). Of note, NOTCH1mut was associated with shorter PFS in the O-Chl arm (17.7 vs. 23.3, HR 1.86 p=0.01) but did not affect PFS in the Chl arm (10.3 vs. 13.3 months, HR 1.20 p=0.49). Correspondingly, in cases without NOTCH1mut a benefit from the addition of Ofatumumab was evident (HR 0.501 p<0.001) while for NOTCH1mut patients a reduced benefit which did not meet statistical significance was observed (HR 0.734 p=0.35). To identify factors of independent clinical impact, we performed multivariable Cox regressions for PFS and OS including the following variables: treatment, gender, age, Binet stage, ECOG status, CIRS, B symptoms, WBC, ß2-MG, 11q, 17p, IGHV and NOTCH1. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.39, p<0.001), WBC > 50Gl/l (HR 2.66, p<0.001), CIRS Score >8 (HR 1.70 p<0.001), male gender (HR 1.39 p=0.04), unmutated IGHV (HR 1.38 p=0.04), 17p- (HR 3.19 p<0.001) and NOTCH1mut (HR 1.47 p=0.05). Regarding OS, WBC > 50Gl/l (HR 2.58 p=0.01), ß2-MG > 5mg/l (HR 2.55 p=0.004), Binet Stage C (HR 2.13 p=0.01), 17p- (HR 4.97 p=0.001) and unmutated IGHV (HR 1.91 p=0.04) were identified as independent prognostic factors. Most likely due to the low frequency of NOTCH1mut of 12%, an interaction term in the multivariable model failed to achieve significance (HR 1.49, p=0.27). When comparing NGS and Sanger sequencing, all cases with a mutant allele burden of >5% were detected by Sanger sequencing and in 34 of 45 NOTCH1mut patients, the hotspot mutation could be identified in a fraction >20%. For this subgroup, the effect of NOTCH1mut on PFS in the O-Chl treatment arm was even more pronounced (O-Chl: HR 2.459, p<0.01). Conclusion In the OMB110911 trial evaluating 1st line O-Chl against Chl, NOTCH1mut was associated with absence of 13q-, +12q, unmutated IGHV and a shorter PFS in multivariable analysis. Comparison of the impact of NOTCH1mut in both treatment arms suggests NOTCH1mut is a predictive marker for reduced benefit from the addition of Ofatumumab in the O-Chl treatment arm. Disclosures: Tausch: GSK: Research Funding, Travel support Other. Off Label Use: First line Ofatumumab in combination with CBL in a clinical trial. Hillmen:GlaxoSmithKline: Honoraria, Research Funding. Offner:GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees. Janssens:Mundipharma: Speakers Bureau; Roche: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Panagiotidis:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Danhauser-Riedl:GlaxoSmithKline GmbH & Co KG: Employment. McKeown:GSK: Employment. Winter:GlaxoSmithKline: Employment, Equity Ownership. Gupta:GSK: Employment. Stilgenbauer:GSK: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel support Other.

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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 ◽

10.1182/blood.v116.21.4024.4024 ◽

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.

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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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Impact of Treatment on Overall Survival (OS) in Higher-Risk Myelodysplastic Syndromes (MDS): A Report from the Erasme Study

Blood ◽

10.1182/blood.v126.23.5240.5240 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5240-5240

Author(s):

Montserrat Arnan ◽

Rosa Coll ◽

Mar Tormo ◽

José María Bastida ◽

María Calbacho ◽

...

Keyword(s):

Prospective Study ◽

Board Of Directors ◽

Real World ◽

Who Classification ◽

Refractory Anemia ◽

Advisory Committees ◽

Prior Therapy ◽

Real World Setting ◽

Very High

Abstract Introduction: Treatment of MDS has undergone a dramatic change in recent years with the emergence of demethylating agents; however, there are limited data on the impact of these agents on OS in the "real-world" setting. The aim of this study is to evaluate the use and outcomes of different therapies in patients (pts) with International Prognostic Scoring System (IPSS)-defined Intermediate-2- and High-risk (higher-risk) MDS. Methods: The ERASME study (CEL-SMD-2012-01) is an observational, prospective study of pts with either MDS or chronic myelomonocytic leukemia (CMML); pts were defined using the 2008 World Health Organization (WHO) classification system. Initial pt management strategy was classified into 3 groups: active therapy (AT), such as chemotherapy or treatment with azacitidine (AZA), lenalidomide (LEN), etc.; allogeneic hematopoietic cell transplantation (HCT), which included those pts receiving other therapies before transplantation; and observation and support (OB&SP), which included red blood cell and platelet transfusions, and growth factors. OS rates of higher-risk pts are presented using the Kaplan-Meier method. Results: A total of 160 pts with higher-risk MDS were recruited between Jan 2013 and Feb 2015. Median follow-up was 8.6 months (interquartile range [IQR] 4.0-11.8). Pt characteristics are described in the Table. AT was the first therapeutic decision in 83 (52%) pts, HCT in 43 (27%), and OB&SP in 34 (21%). Within the AT group, 75 (90%) pts received AZA alone, 5 (6%) AZA plus chemotherapy, and 3 (4%) received other options; most pts (n = 78; 94%) were treated with a 7-day regimen. Among the 43 potential HCT candidates, 40 (93%) had received prior therapy: 25 (58%) with AZA alone, 8 (19%) with chemotherapy, 6 (14%) with AZA plus chemotherapy, and 1 (2%) with LEN; 3 (7%) had not received prior therapy. Of the potential HCT candidates, 20 had undergone transplantation within a median of 8 months (IQR 4.1-13.3); 7 (16%) pts died before transplantation and 16 (37%) are still awaiting transplantation. The main reasons for OB&SP being the initial pt strategy were disease risk (100%), age (95%), comorbidities (60%), and symptomatology (44%). At last follow-up, 70 of 160 pts (44%) had died after a median of 6 months (IQR 2.9-11.8): 34 (41%), 14 (32%), and 22 (65%) pts undergoing AT, HCT, and OB&SP, respectively (log-rank 6.9; P = 0.032). Median OS in pts who received AT, HCT, and OB&SP was 18.60 months (95% confidence interval [CI] 13.1-21.8), 14.92 months (95% CI 11.6-not reached), and 8.44 months (95% CI 4.3-13.4), respectively. Median OS was significantly longer in the AT group compared with the OB&SP group (hazard ratio [HR] 1.9; 95% CI 1.1-3.3; P = 0.0197). No statistically significant difference was observed in OS between pts treated with AT and those considered potential HCT candidates (HR 0.9; 95% CI 0.5-17.7; P = 0.8). Conclusions: The preliminary data from this observational, prospective study indicate that AT significantly prolongs OS compared with OB&SP when treating pts with higher-risk MDS in a real-world setting. AZA was the most common treatment in the AT group. Abstract presented on behalf of the ERASME Study Investigators Group. Table. Baseline characteristics of the MDS population (N = 160) Characteristic Age, median (IQR), years 73 (64.5-79.0) Male, n (%) 86 (53.8) Bone marrow blast count, median (IQR), % 12 (7.5-16.3) Hemoglobin level, median (IQR), g/dL 9.55 (8.0-10.6) Platelet count, median (IQR), × 109/L 64.75 (41.0-121.0) ANC, median (IQR), × 109/L 1 (0.47-2.20) Cytogenetic risk (by IPSS-R), n (%) Low 64 (40.0) Intermediate 9 (5.6) High 27 (16.9) Very High 39 (24.4) Missing data 21 (13.1) WHO classification, n (%) RCMD 17 (10.6) RAEB type 1 28 (17.5) RAEB type 2 94 (58.8) Unclassified 2 (1.3) Missing 1 (0.6) AML 20-30% blasts 18 (11.3) IPSS risk classification, n (%) Intermediate-2 86 (53.8) High 71 (44.4) Missing 3 (1.9) IPSS-R risk classification, n (%) Very Low 4 (2.5) Low 28 (17.5) Intermediate 20 (12.5) High 40 (25.0) Very High 46 (28.8) Missing 22 (13.8) AML, acute myeloid leukemia; ANC, absolute neutrophil count; FAB, French-American-British; IPSS-R, Revised-IPSS; RAEB, refractory anemia with excess blasts; RCMD, refractory anemia with multilineage dysplasia. Disclosures Off Label Use: Azacitidine was used to treat patients who are potential hematopoietic stem cell transplant candidates. Ramos:GlaxoSmithKline: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria. Rafel:Celgene Corporation: Employment. Valcárcel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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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 ◽

10.1182/blood.v128.22.lba-1.lba-1 ◽

2016 ◽

Vol 128 (22) ◽

pp. LBA-1-LBA-1 ◽

Cited By ~ 44

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.

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Real-World Outcomes for Standard-of-Care Treatments in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2021-146250 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4075-4075

Author(s):

Michel Delforge ◽

Marie-Christiane Vekemans ◽

Sébastien Anguille ◽

Julien Depaus ◽

Nathalie Meuleman ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Retrospective Chart Review ◽

Standard Of Care ◽

Real World Data ◽

Advisory Committees ◽

Treatment Regimens

Abstract Background: With the advent of immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and, more recently, anti-CD38 monoclonal antibodies (mAbs), prognosis of patients with multiple myeloma (MM) has improved considerably. Unfortunately, even with these 3 major MM drug classes, most patients ultimately relapse and require further therapy. There remains an incomplete understanding of how patients who have received extensive therapy and with relapsed/refractory multiple myeloma (RRMM) are treated in routine clinical practice, as no standard-of-care exists for these patients, and what the outcomes are in this real-world setting. Objective: This study aims to evaluate the outcomes of patients with triple-class (IMiD, PI and anti-CD38 mAb) and triple-line exposed RRMM using real-world data from patients in Belgium. Methods: A multicenter, observational study, involving 7 non-academic and academic Belgian centers, was conducted based on a retrospective chart review of adult RRMM patients who started subsequent treatment from March 2017 through May 2021 after having received ≥3 lines of therapy including at least an IMiD, a PI, and anti-CD38-directed therapy (tri-exposed). Data were captured in an electronic case report form (Castor EDC). Patients with an ECOG performance status of ≥2, who received prior CAR-T treatment or prior BCMA-targeted therapy, or with a known active or prior history of CNS involvement (or with clinical signs thereof), were excluded. All treatment lines initiated after becoming eligible were used in the analysis. Specifically, all treatment lines for patients meeting the eligibility criteria more than once in their entire follow-up were included as separate observations, with date of treatment initiation as specific baseline for each treatment line. Cox proportional hazards models were fitted to explore the prognostic value with Overall Survival (OS), Progression Free Survival (PFS), and Time to Next Therapy (TTNT). Results: A total of 112 patients with 237 eligible treatment lines were included in the analysis; median follow-up was 16.6 months. In 45% of the initiated treatment lines, patients were refractory to 4 or 5 therapies, 62% had received ≥5 prior lines, 22% had extramedullary disease and in 48% of observations the time to progression in prior line was shorter than 4 months. After patients became tri-exposed, more than 50 unique treatment regimens were initiated, with the following being the most common: carfilzomib + dexamethasone (14%), pomalidomide + dexamethasone + chemotherapy (8%), and ixazomib + lenalidomide + dexamethasone (6%). Additionally, 4% of included observations were exposed to anti-BCMA agents. Overall, the following treatment classes were the most frequently started: PI only (19%), PI + IMiD combinations (17%), and regimens including anti-CD38 antibodies (15%). Median OS was 9.79 months [95% CI: 7.79; 12.22], median PFS was 3.42 months [95% CI: 2.79; 4.27], median TTNT was 3.61 months [95% CI: 3.09; 4.57]. Higher refractory status (p<0.001), being male (p=0.001), older age (p<0.001), shorter duration of prior lines (p<0.001), shorter time to progression in prior line (p=0.025), and higher LDH levels (p<0.002) were prognostic for worse outcomes for both OS (Figure 1) and PFS. Conclusions: This retrospective chart review of patients with tri-exposed RRMM in Belgium shows that real-world outcomes in terms of OS, PFS and TTNT are poor for these patients, with a median OS of <10 months. A wide variety of treatment regimens used in clinical practice confirm the absence of a clear standard-of-care in this patient population. The literature also confirms that these poor outcomes observed in Belgium, for this subset of MM patients, are similar in other countries. These real-world data highlight the high unmet medical need in this patient population and critical need for new and effective treatment options. MD and MCV contributed equally to this work. Figure 1 Figure 1. Disclosures Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Vekemans: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceutica: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Depaus: Takeda: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Meuleman: iTeos Therapeutics: Consultancy. Strens: Realidad bvba: Consultancy. Van Hoorenbeeck: Janssen: Current Employment. Moorkens: Janssen-Cilag: Current Employment. Diels: Janssen: Current Employment. Ghilotti: Janssen-Cilag SpA, Cologno Monzese, Italy: Current Employment. Dalhuisen: Janssen: Current Employment. Vandervennet: Janssen: Current Employment.

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Real-World Outcomes for Pediatric and Young Adult Patients with Relapsed or Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (ALL) Treated with Tisagenlecleucel: Update from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Blood ◽

10.1182/blood-2021-146393 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 428-428

Author(s):

Samuel John ◽

Michael A. Pulsipher ◽

Amy Moskop ◽

Zhen-Huan Hu ◽

Christine L. Phillips ◽

...

Keyword(s):

Clinical Trial ◽

T Cell ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Ad Hoc ◽

Age Groups ◽

Advisory Committees ◽

Advisory Boards

Abstract Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy indicated in the USA for treatment of patients up to 25 years (y) of age with B-cell ALL that is refractory or in second or later relapse. Overall response rate was 82% with 24 months' (mo) follow-up in the registrational ELIANA trial [Grupp et al. Blood 2018]; pooled data from ELIANA and ENSIGN revealed similar outcomes upon stratification by age (<18y and ≥18y) [Rives et al. HemaSphere 2018]. Early real-world data for tisagenlecleucel from the CIBMTR registry reported similar efficacy to ELIANA with no new safety signals [Pasquini et al. Blood Adv 2020]. Outcomes are reported here for patients who received tisagenlecleucel in the real-world setting, stratified by age (<18y and ≥18y). Methods: This noninterventional prospective study used data from the CIBMTR registry and included patients aged ≤25y with R/R ALL. Eligible patients received commercial tisagenlecleucel after August 30, 2017, in the USA or Canada. Age-specific analyses were conducted in patients aged <18y and ≥18y at the time of infusion. Efficacy was assessed in patients with ≥12mo follow-up at each reporting center and included best overall response (BOR) of complete remission (CR), duration of response (DOR), event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). Safety was evaluated in all patients who completed the first (100-day) assessment. Adverse events (AEs) of interest - including cytokine release syndrome (CRS) and neurotoxicity - were monitored throughout the reporting period. CRS and neurotoxicity were graded using the ASTCT criteria. Results: As of October 30, 2020, data from 451 patients were collected, all of whom received tisagenlecleucel. The median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25-34). Patients aged ≥18y appeared to have greater disease burden at baseline than those aged <18y, indicated by lower rates of morphologic CR and minimal residual disease (MRD) negativity prior to infusion. Older patients were also more heavily pre-treated before infusion. All other patient characteristics at baseline were comparable between the two groups (Table 1). In the efficacy set (median follow-up 21.5mo; range 11.9-37.2; N=322), BOR of CR was 87.3% (95% CI 83.1-90.7); MRD status was available for 150 patients, of whom 98.7% were MRD negative. Median DOR was 23.9mo (95% CI 12.3-not estimable [NE]), median EFS was 14.0mo (9.8-24.8) and median RFS was 23.9mo (13.0-NE); 12mo EFS and RFS were 54.3% and 62.3%, respectively. For OS, the median was not reached. Efficacy outcomes were generally similar across age groups (Table 1). In the safety set (median follow-up 20.0mo; range 2.6-37.2; N=400), most AEs of interest occurred within 100 days of infusion. Any-grade CRS was observed in 58.0% of patients; Grade ≥3 in 17.8%. Treatment for CRS included tocilizumab (n=113; 28.3% of all patients) and corticosteroids (n=31; 7.8%). Neurotoxicity was observed in 27.3% of patients; Grade ≥3 in 10.0%. Treatment for neurotoxicity included tocilizumab (n=17; 4.3% of all patients) and corticosteroids (n=28; 7.0%). During the reporting period, 82 (20.5%) patients died; the most common cause of death was recurrence/persistence/progression of primary disease. CRS and chimeric antigen receptor (CAR)-T cell-related encephalopathy syndrome were the primary cause of death in 2 patients and 1 patient, respectively. Overall, safety data were similar across age groups, although more patients aged ≥18y experienced any-grade CRS or neurotoxicity and were subsequently treated (Table 1). Conclusions: Updated registry data for pediatric and young adult patients with R/R ALL treated with tisagenlecleucel revealed that patients aged ≥18y had a greater disease burden and were more heavily pre-treated at baseline than patients aged <18y. The overall efficacy and safety profiles of commercial tisagenlecleucel reflected those observed in the clinical trial setting [Grupp et al. Blood 2018; Rives et al. HemaSphere 2018] and were broadly consistent across age groups. Some important differences between the <18y and ≥18y groups were identified, which may point to challenges in timely identification and/or referral of older patients for CAR-T cell therapy. Figure 1 Figure 1. Disclosures Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Margossian: Cue Biopharma, Inc.: Current Employment; Novartis: Other: Ad hoc Advisory Boards. Nikiforow: Kite/Gilead: Other: Ad hoc advisory boards; Novartis: Other: Ad hoc advisory boards; Iovance: Other: Ad hoc advisory boards; GlaxoSmithKline (GSK): Other: Ad hoc advisory boards. Martin: Novartis: Other: Local PI for clinical trial; Bluebird Bio: Other: Local PI for clinical trial. Rouce: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Pfizer: Consultancy. Tiwari: Novartis Healthcare private limited: Current Employment. Redondo: Novartis: Current Employment. Willert: Novartis: Current Employment. Agarwal: Novartis Pharmaceutical Corporation: Current Employment, Current holder of individual stocks in a privately-held company. Pasquini: Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Kite, Vertex, and Servier: Research Funding; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding.

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The Impact from Frontline CLL Chemo Immunotherapy Regimen Outcomes Based on Patient Tolerability

Blood ◽

10.1182/blood-2018-99-119462 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5551-5551

Author(s):

Jake Towriss ◽

Prosanta Mondal ◽

Waleed Sabry ◽

Mohamed Elemary ◽

Hadi Alphonse Goubran ◽

...

Keyword(s):

Patient Outcome ◽

Board Of Directors ◽

Real World ◽

Cox Regression ◽

Dose Intensity ◽

Front Line ◽

Advisory Committees ◽

Cox Regression Analysis ◽

Choice Of Treatment ◽

Number Of Cycles

Abstract Background: The addition of anti-CD20 monoclonal antibodies to chemotherapy regimens for Chronic Lymphocytic Leukemia (CLL) has led to significant improvements in response and survival (Burger, O'Brian, Nat Rev Clin Oncol 2018). However, toxicities with treatment exist and real world evidence suggests that tolerability of treatment protocols may differ than those established by clinical trials (Mato et. al. Am Soc Hematology 2017), making clinical treatment decisions challenging. This study retrospectively reviewed the tolerability of three front line chemo-immunotherapy options utilized at the Saskatchewan Cancer Agency (SCA): Fludarabine, Cyclophosphamide and Rituximab (FCR) for fit patients, Bendamustine plus Rituximab (BR) for older but fit patients or younger but frail and Obinutuzumab plus Chlorambucil (O-Chlor) for older and/or frail patients. SCA guidelines suggest the choice of treatment regimen should be based on patient age and fitness, a surrogate for ability to tolerate full dose treatment. However, neither these two criteria nor what constitutes tolerability is defined, resulting in a subjective assessment of fitness, a common problem in real world settings (Bouret et al, Hematologica 2013). We hypothesized that choice of treatment without these definitions would lead to poor choice of regimen selection and inferior patient outcome. Methods: We retrospectively reviewed the electronic medical records of CLL patients receiving front line chemo immunotherapy treatment at the SCA between 2015-2018. Patients' ability to tolerate treatment was assessed by the number of cycles completed, total dose intensity received, dose delays or change in therapy. Regimen tolerability was compared to physician calculated Cumulative Illness Rating Scale (CIRS) scores (an objective fitness measure) however, this was calculated after treatment regimen was determined. Kaplan-Meier analysis, univariable and multivariable Cox regression models were utilized to analyze the effect of tolerability and regimen received on patient outcome as defined by death due to CLL or progressive disease. Results: Ninety-six patient charts were reviewed. Regimen tolerability is shown in Table 1. A dose intensity of ≥ 75% was achieved by 91.3%, 69.9% and 48.7% of patients treated with FCR, BR and O-Chlor respectively. Dose intensity was statistically different among all 3 treatments (p=0.002) and specifically between FCR and BR (p=0.048). The number of cycles received for the 3 treatment groups were also statistically different most notably between FCR and O-Chlor (p=0.01) CIRS score of ≤ or > 6 was not different between the 3 groups. Median survival was statistically different between FCR (34.5 mo.), BR (36.1 mo.) and O-Chlor (25.4mo), (p=0.02) by Kaplan Meir Analysis. Univariate Cox regression analysis demonstrated the following statistically significant risk differences for death from CLL or disease progression; 1) Higher risk for O-Chlor versus BR [Hazard Ratio (HR)= 5.16, 95% confidence interval (CI): (1.65-16.13), P=0.004), 2) Lower risk for DI ≥ 75% for a 3 regimens [HR=0.19, 95% CI: (0.08-0.44), P=0.001], 3) each additional cycle of treatment received lowered the risk of death from CLL or disease progression by 33% [HR=0.67, 95% CI:(0.56-0.80), P<0.0001] and 4) if an additional cycle of treatment required dose reduction, the event rate decreased by 23% [HR=0.77, 95% CI: (0.59-0.99), P=0.047]. Multivariable Cox regression analysis demonstrated that only the regimen received and not specific tolerability remained statistically significant for patient outcomes. Conclusions: Dose intensity and the number of cycles received independently affected patient outcome indicating that certain aspects of regimen tolerability are important to consider when making treatment decisions. These results add to the growing body of real world evidence for front line CLL chemo immunotherapy. Disclosures Elemary: Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity's Board of Directors or advisory committees.

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Final Overall Survival Results of a Randomized Trial Comparing Bortezomib Plus Pegylated Liposomal Doxorubicin with Bortezomib Alone in Subjects with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.3448.3448 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3448-3448

Author(s):

Robert Z. Orlowski ◽

Arnon Nagler ◽

Pieter Sonneveld ◽

Joan Bladé ◽

Roman Hajek ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Pharmaceutical Research ◽

Phase Iii ◽

Advisory Committees ◽

Grant Support ◽

Johnson Pharmaceutical Research

Abstract Introduction Previous results of an open-label, randomized, controlled, multicenter phase III study (DOXIL-MMY-3001) demonstrated that bortezomib+pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in treating subjects with relapsed or refractory multiple myeloma (MM) whose disease had failed one or more lines of prior therapy. The risk of developing disease progression was significantly reduced by 45% with bortezomib+PLD (median time to progression (TTP) with bortezomib+PLD: 9.3 months, bortezomib: 6.5 months; HR=1.82, 95% confidence interval (CI) [1.41, 2.35]; p=0.000004). In the interim analysis, the 15-month overall survival (OS) rate for bortezomib+PLD was 76% (95% CI [70%, 83%]) compared with 65% (95% CI [58%, 73%]) for bortezomib alone (p=0.03)(Orlowski et al JCO 25: 3892-3901, 2007). A protocol-defined analysis of the final survival data of this study is provided here. Methods Subjects with confirmed MM, ECOG status 0 to 1, platelets ≥75,000/mm3, hemoglobin ≥8.0 g/dL, absolute neutrophils ≥1,000/mm3, and creatinine clearance ≥30 mL/min were randomized to bortezomib (bortezomib 1.3 mg/m2, intravenous, days 1, 4, 8, and 11 of an every 21-day cycle), or bortezomib+PLD (same bortezomib+PLD 30 mg/m2 intravenous on day 4). Randomization was stratified according to serum β2-microglobulin levels (≤2.5, >2.5 and ≤5.5, or >5.5 mg/L) and response to prior treatment (response followed by progression, or primary refractory). The primary endpoint was TTP; secondary efficacy endpoints included overall survival, progression-free survival (PFS) and overall response rate (complete response [CR] + partial response [PR]). Results A total of 646 subjects (bortezomib+PLD: 324; bortezomib: 322) were randomized between December 2004 and March 2006. In the pre-planned interim analysis, the study met its primary and other secondary end points. The study continued for long-term survival follow-up. At the clinical cutoff of 16 May, 2014, for the final survival analysis with a median follow-up of 103 months, 79% of subjects were dead (bortezomib+PLD: 253 [78%]; bortezomib: 257 [80%]), 6% withdrew consent, 4% were lost to follow-up, and 11% were still alive. Median OS in bortezomib+PLD–treated subjects was 33.0 months (95% CI [28.9, 37.1]) versus 30.8 months (95% CI [25.2, 36.5]) in bortezomib-treated subjects (HR=1.05, 95% CI [0.88, 1.25]; p=0.6068). The types of salvage therapies utilized included dexamethasone (49.1%), thalidomide (31.0%), cyclophosphamide (28.5%), melphalan (22.9%), lenalidomide (21.8%), bortezomib (20.4%) and doxorubicin (8.0%), which were well-balanced between the two treatment groups. Conclusion Despite inducing a superior TTP, long-term follow-up revealed that PLD+bortezomib-treatment did not improve the OS compared with bortezomib alone in subjects with relapsed or refractory MM. The inability to confirm the early survival advantage may be due to the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase III trials. Disclosures Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Orthobiotech;: Consultancy. Bladé:Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Spencer:Hospira: Research Funding. Robak:MorphoSys AG: Research Funding. Dmoszynska:Johnson & Johnson Pharmaceutical Research & Development: Research Funding. Horvath:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Research Funding. Sutherland:OrthoBiotech: Consultancy. Xiu:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Employment, Equity Ownership. Parekh:Johnson & Johnson Pharmaceutical Research & Development: Employment, Equity Ownership. Miguel:Janssen Cilag: Consultancy, Honoraria.

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