IMBRUVICA is a kinase inhibitor indicated for the treatment of adult patients with:...Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion

Recommendations: TP53 mutation or del(17p): ibrutinib or acalabrutinib or venetoclax plus obinutuzumab or venetoclax alone or idelalisib plus rituximab [III, A].

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma...SUGGESTED TREATMENT REGIMENS...CLL/SLL with del(17p)/TP53 mutation…FIRST-LINE THERAPY…Other recommended regimen…Ibrutinib...

When comparing ibr-treated pts with specified high-risk genomic features vs those without, PFS and ORR were comparable in the different subgroups, including pts with unmutated vs mutated IGHV (PFS HR, 1.79, 95% CI 0.99-3.24) or mutated vs not mutated NOTCH1 (PFS HR, 1.05, 95% CI 0.65-1.69) (Table). Improved outcome was also noted for pts with del(17p)/TP53 mutated/BIRC3 mutated, the highest risk category per Rossi 2013 (HR 1.05, 95% CI 0.54-2.04)...This integrated analysis of pts undergoing first-line ibr-based treatment, with up to 79 mo follow up, demonstrated similar PFS and ORR for ibr-treated pts with or without high-risk genomic features, and confirmed significant PFS and ORR benefits with ibr-based therapy versus clb (± obinutuzumab).

At 42 mo, PFS rates were significantly higher across high-risk genomic subgroups in ibr-treated pts (63-82%) compared with clb treated pts (6-34%), and consistent PFS benefit with ibr was observed across all high-risk genomic subgroups....Improved outcome was also noted for pts with del(17p)/TP53 mutated/BIRC3 mutated, the highest risk category per Rossi 2013 (HR 1.05, 95% CI 0.54-2.04).

CONTRADICTED EVIDENCE: Patients had documented CLL/SLL and a documented cytogenetic test performed prior to ibrutinib start date confirming the presence or absence of del(17p). There were 1,037 first-line ibrutinib treated patients included based on the above inclusion criteria, 24% of patients had del(17p) present. Based on the significant impact shown on OS, and to a lesser degree TTNT and TTD, these data confirm that del(17p) is a negative predictive factor in this setting.

At 42 months a significantly higher proportion of ibrutinib-treated patients with deletion(17p)/TP53 mutations, deletion(11q), or unmutated IGHV were progression-free compared to patients with these genomic features who were treated with chlorambucil (Figure).

Patients who received ibrutinib-based therapy (versus idelalisib-based therapy) as their first KI experienced a significantly better PFS in all settings; front-line (HR 2.8, CI 1.3–6.3, P = 0.01), relapsed-refractory (HR 2.8, CI 1.9–4.1, P < 0.001), del17p (HR 2.0, CI 1.2–3.4, P = 0.008), or complex karyotype (HR 2.5, CI 1.2–5.2, P = 0.02).

...Del 17p by fluorescence in situ hybridization (FISH) or TP53 mutation by polymerase chain reaction (PCR) or Next Generation Sequencing...

Eligible patients were ≥ 18 years, with a confirmed diagnosis of CLL/SLL, and who initiated ibrutinib therapy...in previously untreated patients with del17p and/or TP53 mutation, or in patients with relapsed or refractory disease R/R….Median PFS was 47.5 months (48.5/51.6 months in pro/ret). LOT and age (≤ 75 vs > 75 years) were statistically significant predictive factors for PFS. In patients with 0, 1, 2, and ≥ 3 prior LOT, median PFS was: not estimable (NE), 53.9 months, 47.5 months, and 33.5 months, respectively (Figure). At 48 months’ follow-up, ORR was 91.4%....In this longer follow-up of the real-world FIRE study reflecting clinical practice in France, ibrutinib was shown to be an effective treatment for patients with CLL/SLL, and patients who received ibrutinib in earlier LOT achieved better PFS.

Among patients who experienced disease progression on ibrutinib treatment (n = 19), 11 (57.9%) patients carried del(17p)/TP53 mutation, 4 (23.5%) patients had del(11q), and 3 (27.3%) patients harbored unmutated IGHV.

One hundred TN CLL patients were recruited in this study....Seventy-seven patients were IGHV unmutated, 33 displayed only 17p-, 22 only TP53m and 45 both 17p- and TP53m....The overall response rate was 84%, including 10% of complete remissions.

In the CLL cohort...59.1%, had del17p and/or TP53 mutation, and 72.5% had no IGHV mutation. The median PFS for CLL was 38.3 months (51.5/not reached [NR] months in the pro/ret cohorts). ORR was 90.0% (complete response [CR] 16.7%, partial response [PR] 51.6%...

Seventy-seven patients were IGHV unmutated, 33 displayed only 17p-, 22 only TP53m and 45 both 17p- and TP53m….The overall response rate was 84%, including 10% of complete remissions...The 12, 24 and 36-month PFS was 91%, 82% and 75%, respectively….ibrutinib in TN CLL patients with TP53 abnormalities, confirming the efficacy of ibrutinib in this subset of patients.

...29 CLL/SLL patients were enrolled in this cohort with 27 CLL and 2 SLL….4 patients had del(17p) and/or TP53 mutation (13.8%), 7 patients had del(11q) (24.1%), 7 had NOTCH1 mutation (24.1%) and 7 had MYD88 mutation (24.1%)….All four patients with TP53 abnormalities achieved PR and two of them (50.0%) achieved uMRD in both PB and BM. One of 6 patients with del(11q) achieved CR (16.7%) and five achieved PR (83.3%), with 2 achieved uMRD in both PB and BM (33.3%)....

...previously-untreated CLL patients, enriched for high-risk genomic features, reflects the initial approval of ibrutinib for the treatment of first-line patients with del17p in Spain. Single-agent Ibrutinib as the first-line treatment in this real world population was effective regardless of risk factors and well tolerated, with a low rate of discontinuation due to toxicity. Findings are consistent with those reported in clinical trials.

27 treatment-naïve CLL patients with 17p deletion and/or TP53 mutation received ibrutinib, alone (n=15) or in combination with rituximab (n=12)….Our data demonstrate that frontline therapy with ibrutinib results in long-term remissions in high-risk CLL patients with 17p deletion and/or TP53 mutations, despite the lack of deep remissions, with an estimated 5-year PFS of 66%.

CONTRADICTNG EVIDENCE: Complex karyotype was detected in 38 patients and was associated with del17p in 24 cases (p = 0,0049). Patients with complex karyotype had significantly worse progression free survival (PFS): the median PFS was 34 months versus 40 months (p=0,00028). Univariate analysis in this sample also showed unfavorable impact of del17p (p=0,00024) and number of previous therapy lines ≥2 (p=0,027) on PFS, while age, sex, stage and ECOG status were not significant.

CONTRADICTING EVIDENCE: Del(17p)/TP53 mutation demonstrated a trend towards shortened EFS (HR=1.27, p=0.125) and significantly shorter OS (HR=1.88, p=0.008). CLL-CI≥3 and CIRS≥7 showed similar independent associations with worse EFS and OS (Table). Median EFS and OS were shorter in patients with high CLL-CI score (Fig).

The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups....efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL.

With a median follow-up of 28 months, overall response rate was 85% and estimated 30-month progression-free and overall survival rates were 57% [95% confidence interval (CI) 50-64] and 69% (95% CI 61-75)...Progression-free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL.

del(17p) was detected in four (5%) of 83 patients and TP53 mutations....ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23-0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone)...Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients.

...previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib…A high proportion of patients had an overall response to ibrutinib and the risk:benefit profile was favourable…