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).

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 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).

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.

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%.

...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.

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).

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.

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.

...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…