Performance of Standard Prognostic Models in Older Adults Receiving Ibrutinib for Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL): A Post Hoc Analysis of Alliance A041202 Phase 3 Trial

Background

CLL International Prognostic Index (CLL-IPI) is a weighted scoring system combining five prognostic factors that was developed for risk stratification of TN CLL in the era of chemoimmunotherapy [CLL-IPI Working Group. Lancet Oncol 2016]. Recently, the four-factor model (CLL4) was validated in patients (pts) receiving ibrutinib, primarily for the treatment of relapsed or refractory CLL [Ahn et al. J Clin Oncol 2021]. Data on model performance are limited when ibrutinib is used as first-line therapy. Here we evaluated CLL4 and CLL-IPI in TN CLL pts aged 65 years or older in the Alliance A041202 trial (NCT01886872) [Woyach et al. N Engl J Med 2018].

Methods

Pts were randomized to bendamustine plus rituximab (BR group) or ibrutinib-based therapy with or without rituximab (I/IR group). The CLL4 score was determined for individual pts by assigning 1 point each to the presence of TP53 aberration, β-2 microglobulin (B2M) ≥5 mg/L, elevated lactate dehydrogenase (LDH), and prior treatment, and summing over points; risk categories were low (0-1), intermediate (2), and high (3-4). We utilized the first three factors of CLL4 since all pts were previously untreated. The CLL-IPI score was determined based on the presence of TP53 aberration (4 points), B2M >3.5 mg/L (2 points), unmutated IGHV (2 points), age >65 years (1 point), and Rai stage I-IV (1 point), and summing over points; risk categories were low (0-1), intermediate (2-3), high (4-6), and very high (7-10). Two of five CLL-IPI risk factors contributed little information since all pts had Rai stage I-IV and nearly all had age >65 years. The primary endpoint for risk stratification was progression-free survival (PFS). We used Kaplan-Meier estimates and Cox proportional hazards models for analyses.

Results

Of 547 pts randomized, 472 pts had a complete set of data required for the calculation of CLL4 scores. The median age was 71 years, and 92% were older than 65 years. 12% had TP53 aberration including deletion 17p and TP53 mutation. Of 334 pts with known IGHV status, 61% had unmutated IGHV. The median follow-up for PFS was 4.5 years. In these 472 pts, 359 (76%) were low risk, 99 (21%) intermediate risk, and 14 (3%) high risk. In the BR group, PFS was significantly shorter for intermediate/high risk CLL4 than low risk (HR 2.43, 95% CI 1.55-3.79, p=0.0001). However, differences in PFS were less apparent for the I/IR group (HR 1.60, 95% CI 1.00-2.56, p=0.05).

In 334 pts in whom CLL-IPI scores could be calculated, 6 (2%) were low risk, 38 (11%) intermediate risk, 262 (78%) high risk, and 28 (8%) very high risk. In the BR group, PFS was significantly shorter for high risk CLL-IPI than intermediate risk (HR 3.73, 95% CI 1.16-12.04, p=0.03) and for very high risk CLL-IPI than high risk (HR 6.05, 95% CI 2.80-13.08, p<0.0001). However, there were no significant PFS differences for the I/IR group (high risk CLL-IPI vs intermediate risk: HR 1.33, 95% CI 0.53-3.33, p=0.54; very high risk CLL-IPI vs high risk: HR 1.21, 95% CI 0.48-3.02, p=0.69).

We next assessed individual components of the prognostic models in the 334 pt subset including both BR and I/IR groups (Table). Variables significantly associated with PFS were B2M, elevated LDH, and unmutated IGHV when controlling for the treatment group. In contrast, TP53 aberration conferred a poor prognosis in the BR group, but not in the I/IR group (interaction test, p=0.008), indicating first-line therapy with ibrutinib can improve the outcome of TP53 aberrant CLL to levels seen in pts without the aberration. In a multivariable model, the interaction between TP53 aberration and the treatment group remained significant. All adverse risk factors except elevated LDH maintained their independent prognostic value.

Conclusions

Neither CLL4 nor CLL-IPI effectively discriminated PFS of older adults receiving ibrutinib-based therapy for TN CLL. When given as a first-line treatment, ibrutinib can overcome the poor prognostic impact of TP53 aberration. IGHV mutation status and B2M had independent prognostic value in our dataset.

Support: U10CA180821, U10CA180882, U24CA196171; Pharmacyclics, An AbbVie Company

Clinicaltrials.gov identifier: NCT01886872

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