Table 1 Outcomes from selected phase II and III trials evaluating continuous BTK inhibitor regimens in untreated CLL [5,6,7, 9, 10, 70, 22, 30, 31, 26, 23].

From: First-line treatment for CLL in the era of targeted therapy

Trial

N

Patients

Arms

Outcomes

RESONATE-2 [23, 70]

229

Untreated CLL,

>65 years without del(17p)

• Ibrutinib

• Chlorambucil

9-year PFS: 49.7% versus 4.4%, favoring ibrutinib.

9-year OS: 68.0% for ibrutiniba.

OS was significantly longer for patients treated with ibrutinib versus chlorambucil in patients with ≥1 high prognostic risk factor, including mutated TP53, uIGHV, and del(11q).

Alliance A041202 [22]

547

Untreated CLL,

≥65 years

• Ibrutinib

• IR

• BR

Median PFS at a median follow-up of 55 months:

Ibrutinib/IR: NR.

BR: 44 months.

No difference in PFS for patients treated with ibrutinib regimens with or without del(17p) or TP53mut (HR: 0.99; 95% CI: 0.51–1.91; P = 0.98).

iLLUMINATE [5]

229

Untreated CLL,

≥65 years or

<65 years with one of: a CIRS score >6, CrCl <70 ml/min, del(17p), or mutated TP53

• Ibr-Obi

• Clb-Obi

Median PFS at a median follow-up of 45 months:

Ibr-Obi: NR.

Clb-Obi: 22 months.

No difference in PFS for patients treated with Ibr-Obi with or without del(17p) or TP53mut (HR: 0.93; 95% CI: 0.32–2.69; P = 0.895).

E1912 [9]

529

Untreated CLL,

≤70 years without del(17p)

• IR

• FCR

5-year PFS rates:

IR: 78%.

FCR: 51%.

Superior PFS with IR compared with FCR in patients with mIGHV and uIGHV.

FLAIR [10]

771

• Untreated CLL, 18–75 years with a WHO performance status of ≤2; patients with del(17p) in >20% of their CLL cells were excluded

• IR

• FCR

4-year PFS rates:

IR: 85.6%.

FCR: 73.0%.

Superior PFS with IR compared with FCR in patients with uIGHV but not mIGHV.

ELEVATE-TN [6, 30]

535

Untreated CLL,

≥65 years or

18–65 years with comorbidities (CIRS-G score >6, CrCl 30–69 ml/min by Cockcroft–Gault)

• Acalabrutinib

• Acala-Obi

• Clb-Obi

72-month PFS (all patients):

Acalabrutinib: 61.5%.

Acala-Obi: 78.0%.

Clb-Obi: 17.2%.

No difference in PFS with acalabrutinib and Acala-Obi for uIGHV versus mIGHV. With Acala-Obi, PFS was numerically lower in patients with versus without del(17p) and/or TP53 mutations, but similar across groups with acalabrutinib.

SEQUOIA [7, 31, 26]

479

Untreated CLL,

≥65 years or

<65 years with one of: a CIRS score >6, CrCl <70 ml/min, or history of severe or frequent infections

Patients with del(17p) were treated with zanubrutinib

• Zanubrutinib

• BR

Patients without del(17p) – randomized:

60-month PFS: 75.8% versus 40.1%, favoring zanubrutinib.

Patients with del(17p) – zanubrutinib:

60-month PFS: 72.2%.

  1. aOS follow-up in the chlorambucil arm was discontinued after a median of 5 years of follow-up for patients with progressive disease.
  2. Acala-Obi acalabrutinib-obinutuzumab, BR bendamustine-rituximab, BTK Bruton’s tyrosine kinase, CI confidence interval, CIRS Cumulative Illness Rating Scale, CIRS-G CIRS-Geriatric, Clb-Obi chlorambucil-obinutuzumab, CLL chronic lymphocytic leukemia, CrCl creatinine clearance, FCR fludarabine-cyclophosphamide-rituximab, HR hazard ratio, Ibr-Obi ibrutinib-obinutuzumab, IGHV immunoglobulin heavy chain variable, IR ibrutinib-rituximab, mIGHV mutated IGHV, mut mutated, NR not reached, OS overall survival, PFS progression-free survival, uIGHV unmutated IGHV, WHO World Health Organization.
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