Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular ...BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinicobiological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: i) early-stage patients (watch-and-wait arm of the CLL1 trial) (n=592); ii) patients in need of treatment, enrolled in 3 phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1861). Subset #1 was associated with del(11q), higher CLL international prognostic index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (HR: 4.2, CI: 2-8.6, p<0.001), and shorter time-to-next-treatment (TTNT) in the advanced-stage cohort (HR: 2, CI: 1.2-3.3, p=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M-CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset # 2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients.
Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this ...open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized (1:1) to receive either 1-year venetoclax-obinutuzumab (Ven-Obi, 216 patients) or chlorambucil-Obi (Clb-Obi, 216 patients) therapy (NCT02242942). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included minimal residual disease (MRD) and overall survival. RNA sequencing of CD19-enriched blood was conducted for exploratory post-hoc analyses. After a median follow-up of 65.4 months, PFS is significantly superior for Ven-Obi compared to Clb-Obi (Hazard ratio HR 0.35 95% CI 0.26-0.46, p < 0.0001). At 5 years after randomization, the estimated PFS rate is 62.6% after Ven-Obi and 27.0% after Clb-Obi. In both arms, MRD status at the end of therapy is associated with longer PFS. MRD + ( ≥ 10
) status is associated with increased expression of multi-drug resistance gene ABCB1 (MDR1), whereas MRD6 (< 10
) is associated with BCL2L11 (BIM) expression. Inflammatory response pathways are enriched in MRD+ patient solely in the Ven-Obi arm. These data indicate sustained long-term efficacy of fixed-duration Ven-Obi in patients with previously untreated CLL. The distinct transcriptomic profile of MRD+ status suggests possible biological vulnerabilities.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) can induce long-term remissions in patients with chronic lymphocytic leukemia. Treatment efficacy with Bruton's tyrosine ...kinase inhibitors was found similar to FCR in untreated chronic lymphocytic leukemia patients with a mutated immunoglobulin heavy chain variable (IGHV) gene. In order to identify patients who specifically benefit from FCR, we developed integrative models including established prognostic parameters and gene expression profiling (GEP). GEP was conducted on n=337 CLL8 trial samples, "core" probe sets were summarized on gene levels and RMA normalized. Prognostic models were built using penalized Cox proportional hazards models with the smoothly clipped absolute deviation penalty. We identified a prognostic signature of less than a dozen genes, which substituted for established prognostic factors, including TP53 and IGHV gene mutation status. Independent prognostic impact was confirmed for treatment, β2-microglobulin and del(17p) regarding overall survival and for treatment, del(11q), del(17p) and SF3B1 mutation for progression-free survival. The combination of independent prognostic and GEP variables performed equal to models including only established non-GEP variables. GEP variables showed higher prognostic accuracy for patients with long progression-free survival compared to categorical variables like the IGHV gene mutation status and reliably predicted overall survival in CLL8 and an independent cohort. GEP-based prognostic models can help to identify patients who specifically benefit from FCR treatment. The CLL8 trial is registered under EUDRACT-2004- 004938-14 and clinicaltrials gov. Identifier: NCT00281918.
The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve complete remissions and minimal residual disease negativity with ...ibrutinib monotherapy. This multicenter, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumor load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias, anaemia, infusion-related reactions, and diarrhoea. This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an overall response rate of 92%. Ongoing maintenance treatment aims at deeper responses with minimal residual disease negativity. However, ibrutinib should still be used as a single agent outside clinical trials. Clinicaltrials.gov number: NCT02689141.
Purpose
Although minimal residual disease (MRD) is an established surrogate marker for outcomes following treatment with chemoimmunotherapy, less is known about the value of MRD in chemotherapy-free ...treatments in the first-line setting. We investigated the prognostic value of MRD detection after a fixed-duration treatment of venetoclax plus obinutuzumab (VenG) with respect to clinical and genetic risk factors and source of material in previously untreated patients (pts) with CLL and coexisting conditions.
Methods
In this multinational, open-label, Phase 3 trial, 432 previously untreated pts with a Cumulative Illness Rating Scale score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive chlorambucil or venetoclax (216 pts per treatment group) until completion of cycle 12, and in combination with obinutuzumab for the first 6 cycles. The primary endpoint was progression-free survival (PFS), MRD was a secondary endpoint. Peripheral blood (PB) samples for MRD were taken at cycle 7, 9, and 12, and then serially every 3 months. In pts with a treatment response, MRD in bone marrow (BM) was assessed at cycle 9 and 3 months after end of treatment (EOT). MRD was analyzed by quantitative immunoglobulin allele-specific real-time (IGH-ASO)-PCR (cut-off: 10-2 and 10-4) and additionally by next-generation sequencing (NGS, Adaptive Clonoseq assay, cut-off: 10-4, 10-5 and 10-6). Outcome was analyzed according to known MRD risk groups i.e. detectable (≥10-4) and undetectable (<10-4) as well as to known clinical and biological risk factors. Landmark PFS and time to MRD re-detection from EOT were analyzed using Kaplan-Meier methodology. Apart from re-detection to MRD level ≥10-4, pts with a competing event (including progression of disease, relapse, new CLL therapy, and death) also counted towards the MRD re-detection events total.
Results
On the basis of the intention-to-treat population (i.e. for the full trial population and irrespective of sample availability), VenG achieved higher rates of undetectable MRD at EOT compared with chlorambucil and obinutuzumab (ClbG) (PB: 75.5% vs. 35.2%, BM: 56.9% vs. 17.1%). In contrast, detectable MRD in PB was found in 19 (8.8%) VenG pts and 103 (47.7%) ClbG pts. Of these, 11 (5.1%) VenG vs. 47 (21.8%) ClbG pts had intermediate MRD at ≥10-4-<10-2 and 8 (3.7%) vs. 56 (25.9%) pts had high positive MRD at cut-off 10-2. Of the 19 VenG pts with detectable MRD, 64.3% had unmutated IGHV, 22.2% had a TP53 disruption and 17.6% had a complex karyotype. In pts with undetectable MRD in PB, the rate of complete response at EOT was higher with VenG than with ClbG (55.8% vs. 40.8%, Table 1). Achieving undetectable MRD in PB with VenG was associated with a high proportion of patients with corresponding BM clearance of 74.8% with only 4.9% of pts being BM MRD-detectable. In addition, depth of MRD response measured by NGS was more profound in VenG compared to ClbG (<10-5: 67.6% vs. 19.9%, <10-6: 42.1% vs. 6.5%) with undetectable MRD according to both NGS and IGH-ASO-PCR at cut-off 10-4 in 74.5% of pts treated with VenG and an overall concordance between both methods of 95.4%. Considering pts with undetectable MRD in PB at EOT, the time to MRD re-detection was longer with VenG than with ClbG (median 17.7 months and 34 (20.9%) re-detection events with VenG vs. median 7.5 months and 55 (72.4%) re-detection events with ClbG, HR 0.192, 95% CI 0.124-0.296). In landmark analysis from EOT, undetectable MRD correlated with favourable PFS rates at 24 months as compared with detectable MRD: 89.1% vs. 61.9% in VenG and 93.9% vs. 32.6% in ClbG, respectively. Median PFS was not reached in undetectable MRD groups (Figure 1a). Further landmark analysis of PFS by MRD status showed that undetectable MRD translated into improved PFS regardless of the clinical response status at EOT (Figure 1b).
Conclusion
Fixed-duration treatment with VenG achieves unprecedentedly high and sustainable rates of undetectable MRD in patients with previously untreated CLL and coexisting conditions. Findings confirm the prognostic value of MRD assessment at EOT for this chemotherapy-free treatment regimen. Due to high concordance of undetectable MRD in PB and BM in the context of VenG, BM assessments may not be required for these patients.
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Fischer:Roche: Other: travel grants; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritgen:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Al-Sawaf:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Tandon:Roche: Equity Ownership; Roche Products Ltd: Employment. Fink:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Other: travel grants. Stübig:Hexal: Speakers Bureau. Brüggemann:Amgen, Celgene, Janssen: Honoraria, Speakers Bureau; Amgen, Janssen: Membership on an entity's Board of Directors or advisory committees; affimed, Amgen, Celgene, Regeneron: Research Funding; Amgen, Incyte, PRMA: Consultancy. Jiang:Genentech: Employment, Equity Ownership; F. Hoffman-La Roche: Equity Ownership. Schary:Abbvie: Employment, Equity Ownership. Eichhorst:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees. Wendtner:MorphoSys: Consultancy, Honoraria, Research Funding; GILEAD Science: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-CILAG: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Kreuzer:Roche and Abbvie: Honoraria, Other: Expert testimony. Langerak:F. Hoffmann-La Roche Ltd: Research Funding; Gilead: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Genentech, Inc.: Research Funding. Goede:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau; AbbVie: 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, Other: speaker fees, Speakers Bureau; janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau. Böttcher:AbbVie: Honoraria, Other: Travel grants, Research Funding; Celgene: Research Funding; Janssen-CILAG: Honoraria, Other: Travel grants, Research Funding; Roche: Honoraria, Research Funding; Genentech: Research Funding; Becton Dickinson: Research Funding; Novartis: Research Funding. Stilgenbauer:AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Other: Travel support; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau.
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