FRONT LINE (1:12-5:17)
POLARIX Study at ASH 2021
- Randomized clinical trial improving on frontline therapy with Polatuzumab Vedotin an anti-CD79b mAb with cytotoxic agent MMAE
- Results of investigator-assessed PFS with Pola-R-CHP vs R-CHOP
Key Takeaways:
- R-Pola-CHP demonstrates a PFS benefit over R-CHOP
- Absolute risk reduction (2 year PFS) = 6.5% (NNT~15)
- No difference in OS Safety is similar
CNS Prophylaxis (5:18-9:24)
Patients with diffuse B cell may be at risk of relapse in CNS. Is it possible to further reduce the risk?
Risk factors
- IPI – age, performance status, LDH, extranodal disease, stage, plus kidney or adrenal involvement
- Vast majority of patients had <7.4% risk of having a relapse in brain/CNS
- Risk has been further decreased with Rituximab (R-CHOP)
Key Takeaways:
- CNS relapse is an uncommon, but devastating occurrence after R-CHOP in DLBCL
- High-dose Methotrexate (HD-MTX) has at best a small impact on preventing CNS relapse
- IT- therapy may just as good as HD with less toxicity
- [Dr. Jain has] personally stopped recommending it as an academic opinion outside of testicular
Second-line DLBCL (9:25-22:03)
Exciting news outside of standard of care pathway with CAR – T
- ZUMA-7 (axi-cel vs SOC) Locke et al. NEJM 2021
- TRANSFORM (liso-cel vs SOC) Kansas et al. ASH 2021
- BELINDA (tisa-cel vs SOC) Bishop et al. NEJM 2021
Key Takeaways:
- The 3 trials are slightly different with 865 total patients
- Some trials had more/less bridging, some had more transplants but overall similar delivery of CAR T cells and crossover to CAR T cells on SOC arm
Tisa-cel vs axi-cel/liso-cel
- Didn’t not perform as well and didn’t meet primary end point
- Manufacturing not as reliable/quick on trial, although similar % of patients received CAR T
- No explanation for results that is as simple Tisa-cel having lower efficacy
Axi-cel vs liso-cel
- Liso-cel has less CAR T toxicity (CRS, neurotoxicity)
- Follow-up for Liso-cel short, but appears to have good efficacy
- For clinical selection consider:
- manufacturing availability and success rates
- Non-clinical trial “real world” data
- Use of toxicity mitigation strategies (i.e. prophylactic steroids)
Speculation about [near] future treatment of aggressive B cell lymphomas (22:03 -24:20)
Currently approved therapies for DLBCL (In USA)
- Polatuzumab – Bendamustine – Rituximab –
- Tafasitinib (CD19 antibody) – Lenolidomide
- Selinexor
Bispecific Antibodies – connect T cells to tumour
- Non-randomized trials show similar efficacy to CAR T cell therapy with greater convenience and safety, longer treatment duration.
- Combination trials (i.e. Polatuzumab) underway
- Questions remain: long-term durable remission rates, “real world” outcomes, sequencing/combining with CAR T cell therapy are all unknowns
Improvements to CAR cell therapy
- Targets: more targets and bispecific targeting
- Engineering: better CAR activity, better trafficking, less susceptible to exhaustion
- Cell selection: CAR-NK, CAR myeloid/macrophage, CAR gamma/delta T-cells, allogeneic cells
- Clinical: combination therapy with other active agents, improved bridging
