Impact of Minimal Residual Disease on Progression-Free Survival Outcomes after Fixed-Duration Ibrutinib-Venetoclax Versus Chlorambucil-Obinutuzumab in the GLOW Study

Supported by Janssen Research & Development, LLC.PURPOSEIn GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment.METHODSUndetectable MRD (uMRD) was assessed by next-generation sequencing at <1 CLL cell per 10,000 (<10-4) and <1 CLL cell per 100,000 (<10-5) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3).RESULTSIbrutinib + venetoclax achieved deeper uMRD (<10-5) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD (<10-5) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10-4) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD (<10-4) and dMRD (≥10-4) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM.CONCLUSIONMolecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10-4), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time

CLL-106 First Prospective Data on Minimal Residual Disease Outcomes After Fixed-Duration Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for First-Line Treatment of CLL in Older Adult or Unfit Patients: The GLOW Study

Context: Minimal residual disease (MRD) is a predictive marker for progression-free survival (PFS) in chronic leukocytic leukemia (CLL) following chemoimmunotherapy and fixed-duration treatment with venetoclax and anti-CD20 antibodies. This has not been explored for ibrutinib+venetoclax (Ibr+Ven), a fixed-duration treatment with mechanisms of action that synergistically eliminate CLL subpopulations in distinct tumor compartments. Objective: Investigate MRD outcomes at primary analysis of phase 3 GLOW study (NCT03462719). Design: Randomized, open-label, active-control study. Patients: Patients aged ≥65 years or 18–64 years with a CIRS score >6 or creatinine clearance 90% for patients with uMRD<10–4 and patients with detectable MRD; however, Clb+O arm patients with detectable PB MRD relapsed more quickly than those with uMRD<10–4. Conclusions: All-oral, once-daily, fixed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post-treatment versus Clb+O in older adult or unfit patients with previously untreated CLL

CLL-106 First Prospective Data on Minimal Residual Disease Outcomes After Fixed-Duration Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for First-Line Treatment of CLL in Older Adult or Unfit Patients: The GLOW Study

Context: Minimal residual disease (MRD) is a predictive marker for progression-free survival (PFS) in chronic leukocytic leukemia (CLL) following chemoimmunotherapy and fixed-duration treatment with venetoclax and anti-CD20 antibodies. This has not been explored for ibrutinib+venetoclax (Ibr+Ven), a fixed-duration treatment with mechanisms of action that synergistically eliminate CLL subpopulations in distinct tumor compartments. Objective: Investigate MRD outcomes at primary analysis of phase 3 GLOW study (NCT03462719). Design: Randomized, open-label, active-control study. Patients: Patients aged ≥65 years or 18–64 years with a CIRS score >6 or creatinine clearance 90% for patients with uMRD<10–4 and patients with detectable MRD; however, Clb+O arm patients with detectable PB MRD relapsed more quickly than those with uMRD<10–4. Conclusions: All-oral, once-daily, fixed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post-treatment versus Clb+O in older adult or unfit patients with previously untreated CLL

Hydroxymethylation at Gene Regulatory Regions Directs Stem/Early Progenitor Cell Commitment during Erythropoiesis

SummaryHematopoietic stem cell differentiation involves the silencing of self-renewal genes and induction of a specific transcriptional program. Identification of multiple covalent cytosine modifications raises the question of how these derivatized bases influence stem cell commitment. Using a replicative primary human hematopoietic stem/progenitor cell differentiation system, we demonstrate dynamic changes of 5-hydroxymethylcytosine (5-hmC) during stem cell commitment and differentiation to the erythroid lineage. Genomic loci that maintain or gain 5-hmC density throughout erythroid differentiation contain binding sites for erythroid transcription factors and several factors not previously recognized as erythroid-specific factors. The functional importance of 5-hmC was demonstrated by impaired erythroid differentiation, with augmentation of myeloid potential, and disrupted 5-hmC patterning in leukemia patient-derived CD34+ stem/early progenitor cells with TET methylcytosine dioxygenase 2 (TET2) mutations. Thus, chemical conjugation and affinity purification of 5-hmC-enriched sequences followed by sequencing serve as resources for deciphering functional implications for gene expression during stem cell commitment and differentiation along a particular lineage