Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities

Kater, Arnon P.; Owen, Carolyn; Moreno, Carol; Follows, George; Munir, Talha; Levin, Mark‐David; Benjamini, Ohad; Janssens, Ann; Österborg, Anders; Robak, Tadeusz; Šimkovič, Martin; Stevens, Don A.; Voloshin, Sergey; Vorobyev, Vladimir I.; Ysebaert, Loïc; Qin, Rui; Steele, Andrew J.; Schuier, Natasha; Baeten, Kurt; Caces, Donne Bennett; Niemann, Carsten Utoft

doi:10.1056/evidoa2200006

Cited by 118 publications

(107 citation statements)

References 33 publications

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“…The optimal duration of combined ibrutinib and venetoclax is unknown. Some studies have used a xed treatment durations (GLOW (25), CAPTIVATE-FD(26)) while others have utilized an MRD-adapted approach (M.D. Anderson Phase 2(18), CAPTIVATE-MRD(20), HOVON141,( 21) CLARITY (19)).…”

Section: Discussionmentioning

confidence: 99%

Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD

Thompson

Keating

Ferrajoli

et al. 2023

Preprint

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Patients receiving ibrutinib for CLL rarely achieve undetectable measurable residual disease (U-MRD), necessitating indefinite therapy, with cumulative risks of treatment discontinuation due to progression or adverse events. This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥ 12 months (mo) and had ≥ 1 high risk feature (TP53 mutation and/or deletion, ATM deletion, complex karyotype or persistently elevated β2-microglobulin). The primary endpoint was U-MRD with 10− 4 sensitivity (U-MRD4) in bone marrow (BM) at 12mo. Forty-five patients were treated. On intention-to-treat analysis, 23/42 (55%) patients improved their response to CR (2 pts were in MRD + CR at venetoclax initiation). U-MRD4 at 12mo was 57%. Best rate of U-MRD4 was 33/45 (73%); 23/32 stopped ibrutinib; 9 continued ibrutinib. At a median of 41 months from venetoclax initiation, 5/45 patients have progressed; none have died from CLL or Richter Transformation. In 32 patients with BM U-MRD4, peripheral blood (PB) MRD4 was analyzed every 6 months; 10/32 have had PB MRD re-emergence at a median of 13 months post-venetoclax. In summary, the addition of venetoclax in patients treated with ≥ 12mo of ibrutinib achieved high rate of BM U-MRD4 and may achieve durable treatment-free remission.

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Section: Discussionmentioning

confidence: 99%

Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD

Thompson

Keating

Ferrajoli

et al. 2023

Preprint

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“…Based on these data, a randomized phase 3 study (GLOW) compared ibrutinib-venetoclax to chlorambucil-obinutuzumab in 211 previously untreated CLL patients (median age = 71 years, del17p excluded). The estimated 30-month PFS rates were 80% for ibrutinib-venetoclax and 36% for chlorambucil-obinutuzumab, with significantly higher uMRD rate with ibrutinib-venetoclax (52% vs. 17%, respectively) [ 43 ]. In contrast to the CAPTIVATE study, patients in the GLOW trial were older and experienced more AEs (Grade 3/4 AEs of interest in the GLOW study: diarrhea [10%], atrial fibrillation [6%], infections [15%], and hypertension [7%]).…”

Section: Management Of the Patient With Previously Untreated Cllmentioning

confidence: 99%

Chronic lymphocytic leukemia treatment algorithm 2022

Hampel

2022

Blood Cancer J.

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The treatment landscape for patients with chronic lymphocytic leukemia (CLL) has changed considerably with the introduction of very effective oral targeted therapies (such as Bruton tyrosine kinase inhibitors and venetoclax) and next-generation anti-CD20 monoclonal antibodies (such as obinutuzumab). These agents lead to improved outcomes in patients with CLL, even among those with high-risk features, such as del17p13 or TP53 mutation and unmutated immunoglobulin heavy chain (IGHV) genes. Selecting the right treatment for the right patient requires consideration of disease characteristics and prior treatment sequence, as well as patient preferences and comorbidities. The CLL-International Prognostic Index (CLL-IPI) remains the best-validated tool in predicting the time to first therapy among previously untreated patients, which guides selection for early intervention efforts. This review summarizes our current approach to the management of CLL, right from the time of diagnosis through relapsed disease.

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“…16 Older age and comorbidities appear to be asso ci ated with increased rates of car dio vas cu lar toxicities during treat ment with IV. In the GLOW study, 14% had atrial fibrilla tion of any grade and 7% (6 patients) had car diac or sud den deaths, 35 which were higher than the rates reported from the CAPTIVATE study with youn ger patients (4% atrial fibril la tion, <1% or 1 patient with sud den death). 36 The rate of BM-uMRD ranges between 66% and 89% when CD20 mAb is added to the time-lim ited com bi na tions of venetoclax and a BTKi, which has been tested with ibrutinib, acalabrutinib, and zanubrutinib.…”

Section: Table 2 Rates Of Unde Tect Able Min I Mal Resid Ual Dis Ease...mentioning

confidence: 60%

“…34 The GLOW study is a phase 3 study in patients with older age (≥65 years) or comorbidities. 35 The CAPTIVATE study is a phase 2 study in youn ger patients (median age 60 years) with treat ment arms for fixed-dura tion ther apy (15 cycles) and MRD-driven ther apy (15 cycles + con tin u ous therapy based on ran dom i za tion related to MRD sta tus). 36,37 The rate of best bone mar row uMRD (BM-uMRD) was 52% to 66% in these tri als, com pa ra ble to the 57% rate reported from the VO arm of the CLL14 study.…”

Section: Table 2 Rates Of Unde Tect Able Min I Mal Resid Ual Dis Ease...mentioning

confidence: 99%

Selecting initial therapy in CLL

Ahn

Brown

2022

Hematology

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Targeted therapy is a powerful treatment option in chronic lymphocytic leukemia (CLL) that has outperformed conventional chemoimmunotherapy in most clinical settings. Except for selected young, fit patients with a mutated immunoglobulin heavy chain variable region gene, most patients benefit from targeted therapy with either a continuous BTK inhibitor or 1-year fixed-duration venetoclax-obinutuzumab as first-line treatment of CLL. Treatment selection is driven by patient-, treatment-, and disease-related factors, encompassing patient preference, concomitant medications, comorbidities, safety profile of the regimen, and TP53 aberration. Clinical trials are actively investigating the simultaneous inhibition of Bruton’s tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) proteins with or without a CD20 monoclonal antibody, which can achieve deep response in most patients (52%-89% undetectable minimal residual disease in bone marrow).

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Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities

Cited by 118 publications

References 33 publications

Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD

Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD

Chronic lymphocytic leukemia treatment algorithm 2022

Selecting initial therapy in CLL

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