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

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

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).

Overall, this integrated analysis of data with up to 6 years of long-term follow-up demonstrates that using single-agent ibrutinib in earlier lines of treatment results in better PFS, OS, and ORR with sustained efficacy for patients with CLL, including patients with high-risk prognostic features. During this extended follow-up, only 6% of patients treated in the first-line setting discontinued due to progressive disease. Ibrutinib was well tolerated with only 19% of patients across all lines of therapy discontinuing due to AEs.

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).

The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high‐risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080‐0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91%...long‐term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL...

...Cohort 1: Treated and untreated patients age 65 or older and need for therapy Cohort 2: Treated (maximum accrual n=16) and untreated (n=27, evaluable) patients at least 18 years old with 17p deletion or p53 expression by immunohistochemistry or p53 mutation by sequencing analysis....

...- Presence of TP53 mutation as demonstrated by sequencing at the local laboratory and/or presence of 17p deletion as demonstrated by fluorescence in situ hybridization (FISH) testing performed at the local laboratory...

...• TP53 mutated subclone size at WEEK 2,4,12,24,48,72,96 and yearly thereafter compared to baseline [i.e. (TP53 mutated alleles at WEEK 2,4,12,24,48,72,96 and yearly thereafter)/(TP53 mutated alleles at baseline)] • Dimensione del subclone TP53 mutato alle SETTIMANE 2,4,12,24,48,72,96 e poi annualmente rispetto al basale [i.e. (allele TP53 mutato alle SETTIMANE 2,4,12,24,48,72,96 e poi annualmente)/(allele TP53 mutato al basale)]...

...- At least one high-risk cytogenetic feature defined by the presence of 17p deletion, 11q deletion and/or p53 mutation...

With a median follow-up of nearly 10 years, we analyzed efficacy, safety, and depth of response in CLL patients treated with long-term ibrutinib therapy...Among patients with TP53 alterations receiving frontline ibrutinib (N = 34), the mPFS was 81 months with an OS of 69.7% at 117 months….These results further define the long-term prognosis of patients treated with BTK inhibitors for CLL, most notably with substantial improvements in the OS of patients with TP53 alterations over CIT.

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.

There were no significant differences in PFS and OS for pts receiving Ibr alone versus combined Ibr + R (p=0.7833). The 6-year PFS for treatment-naïve (n=27) was 59.3% and 41.2% for R/R pts (n=51); OS was 79.5% and 67.4%, respectively... In this long-term follow-up, patients with CLL and TP53 aberrations treated with ibrutinib had an estimated 6-year PFS and OS of 47% and 72%, respectively. First-line treatment with ibrutinib induced more durable remissions with a 6-year PFS of 59% compared to R/R pts with a PFS of 41%.

Among the 40 pts receiving Ibr alone, 11 pts (27.5%) achieved CR (all with minimal residual disease [MRD], 10-4 sensitivity), 27 pts (67.5%) achieved PR, and 2 pts had stable disease (SD) accounting for an ORR of 95.0%....In this long-term follow-up, patients with CLL and TP53 aberrations treated with ibrutinib had an estimated 6-year PFS and OS of 47% and 72%, respectively. First-line treatment with ibrutinib induced more durable remissions with a 6-year PFS of 59% compared to R/R pts with a PFS of 41%.

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%)....

With a median follow-up of 4 years, first-line ibrutinib-based treatment resulted in sustained efficacy with high PFS and OS rates in CLL pts with TP53 aberration...first-line treatment with ibrutinib has partially overcome the poor prognosis in this high-risk population with 4-year PFS and OS rates of 79% and 88%, respectively (Figure 1B).

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%.

CONTRADICTING EVIDENCE: Patients treated with ibrutinib in phase II and III trials provided the discovery data set...Factors independently associated with inferior PFS and OS were as follows: TP53 aberration, prior treatment, β-2 microglobulin ≥ 5 mg/L, and lactate dehydrogenase > 250 U/L.

Ibrutinib is the only approved novel agent that is available for the treatment of relapsed-refractory and treatment-naive chronic lymphocytic leukemia patients with deletion 17p or TP53 mutation in India. This is the first report of generic ibrutinib to the best of our knowledge and it shows comparable efficacy and safety to innovator ibrutinib.

Patients with high-risk prognostic features were defined as having TP53 mutation, del(11q), and/or unmutated IGHV....For patients with high-risk prognostic features, median PFS was NR for first-line or 1-2 prior lines and was 42.5 months for ≥3 prior lines (Figure 1B); treatment in earlier lines resulted in better PFS for these patients (first-line vs 1-2 prior, HR: 0.64 [95% CI, 0.35-1.18]; first-line vs ≥3 prior, HR: 0.33 [95% CI, 0.19-0.57]; 1-2 prior vs ≥3 prior HR: 0.51 [95% CI, 0.30-0.87])....this integrated analysis of data with up to 6 years of long-term follow-up demonstrates that using single-agent ibrutinib in earlier lines of treatment results in better PFS, OS, and ORR with sustained efficacy for patients with CLL, including patients with high-risk prognostic features

CONTRADICTED 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).

34 patients who had CLL with TP53 alterations were treated with ibrutinib as first-line therapy...As the best response, 30% had a complete response to treatment...At 6 years, the estimated percentage of patients with progression-free survival and overall survival was 61% and 79%, respectively...The data that are summarized here underscore the longer durability of response with ibrutinib than with chemoimmunotherapy

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 results showed that the CI values of ibrutinib combined with curcumin were less than 1 at 24 and 48h, suggesting that ibrutinib combined with curcumin has a synergistic killing effect on CLL cells with TP53 mutation...Ibrutinib combined with curcumin has synergistic killing effect on TP53- mutated CLL cells.

We generated isogenic HG3-Cas9 CLL-derived cell lines harboring monoallelic del(11q) (targeting 11q22.1/11q23.3 regions) and further loss-of-function mutations in ATM and/or TP53 to mimic all the possible combinations observed in our CLL cohort....We next assessed whether these cell models could predict responses of these combined abnormalities to BTK and PI3K inhibitors. We observed that HG3-del(11q) TP53MUT and HG3-TP53MUT cells showed partial response to ibrutinib and idelalisib, although the IC50 values were still higher than the ones observed in HG3WT clones, especially with idelalisib (27.4 and 20.6 vs. 1.8 uM, respectively).