CLL

Risk stratification

1.  CLL IPI score  Very high IPI 7, 10 yr OS=0, low 0-1 10 yr OS=87%

2. The International Prognostic Score for Early-stage CLL (IPS-E) uses three variables (unmutated IGHV, lymphocytes >15,000/microL, palpable lymph nodes) to stratify patients with early stage CLL at diagnosis into three risk groups with differing likelihood of requiring treatment at one and five years .

●Low risk (no risk factors) – <1 percent treated at one year; 8 percent treated at five years

●Intermediate risk (one risk factor) – 3 percent treated at one year; 28 percent treated at five years

●High risk (two or three risk factors) – 14 percent treated at one year; 61 percent treated at five years

1. Aside from TP 53 mutation BIRC 3 mutations are high risk.
2. NOTCH mutation and 11 q are intermediate risk.
3. If TP 53 mutated and also IGHV unmutated, pt have the shortest PFS and OS.

Median OS 

unmutated- 117 months, mutated 293 months

Treatment Naive

3 options:  Zanubrutinib OR Acala with Obin OR Ven Obin

1. Zanu- Sequoia trial: 2 yr PFS  85% versus 70% for BR

2.  Acala- ELEVATE TN: While the OS HR for acalabrutinib-obinutuzumab versus acalabrutinib in a post hoc analysis was noteworthy (HR: 0.53; 95% CI, 0.26, 1.06), the difference between the two acalabrutinib-containing arms was not statistically significant (P = 0.0836). Estimated 48-month OS rates were 92.9% for acalabrutinib-obinutuzumab, 87.6% for acalabrutinib, and 88.0% for obinutuzumab-chlorambucil.

3. CLL 14  Ven+ Obi- ( vs obin chlorambucil) CIRS> 6 CLL 14 2 yr PFS 90% Ven arm compared to single agent obi, 6 yr PFS 53%. For TP 53 mutated PFS 4 yr, unmutated PFS 65 months

4. GLOW trial Ibrutinib+ Ven fixed duration for elderly with CIRS > 6-->3 cycles ibrutinib lead in then 12 months combo

5. FLAIR trial, young new CLL--> MRD guided therapy was individualized. Ibrutinib + Ven versus FCR--9-month complete response rate was 60% for the doublet versus 50% for the chemoimmunotherapy with an overall response rate of 86% versus 76%. OS was better in the Ven+ Ibrutinib.

Relapsed Refractory: if progressing on BTK inhibitor--> Venetoclax+ obin 2 yr, If progression after Ven, depending on time frame after initial rx, consider retreatment. Can go to BTK inhibitor after reassessing genomic profile. 3rd line are pirtobrutinib( DOR 20 months, 80% respond) versus CAR-T ( Liso cel 18% CR, high risk of ICANS and CRS). 

1. Ibrutinib PFS 52 months standard risk; 17 p deleted 26 months; 93% ORR in both TN and RR as single agent

Richter's median OS 3-9 months

https://www.researchtopractice.com/OncologyTodayPostASH24/CLL/Video/1?playlistIndex=0#t=0m0s