A Summary of Day 1 in Lymphoma from ASH 2018

Continuing the trend of the past 4–5 years, chimeric antigen receptor (CAR) T-cell studies are dominating the sessions so much so that organizers this year have split the abstracts into their own sessions. As opposed to updating clinical trial data, at ASH 2018, two groups of investigators looked into real-world evidence regarding the efficacy and toxicity of patients receiving axicabtagene ciloleucel (Axi-Cel), the anti-CD19 CAR T-cell (second generation, CD3-zeta, CD28 co-simulation) in multiply relapsed/refractory aggressive non-Hodgkin lymphoma (NHL) patients (abstracts 91 and 92). In total, they looked at 399 patients (295 in 17 centres and 104 in 6 centres for abstracts 91 and 92, respectively) treated over the past year. A lot of detail was given, but distilling it down, both retrospective studies had very similar outcomes. Both retrospectives found that there was >90% success in CAR T-cell manufacturing with a median of about 21 days between apheresis and CAR T-cell infusion. Objective response rates (ORR) were 81% and 71% in abstracts 91 and 92, respectively; additionally, complete response rates were 57% and 61%, respectively. Median progression-free survival (PFS) was approximately 6 months in both studies with the survival curves showing the same plateau as the pivotal clinical trial, albeit with a quite short follow-up time. What makes the efficacy data more interesting is the fact that these were real-world patients, meaning that 40% and 60% of patients on these abstracts, respectively, would not have been eligible for the ZUMA1 clinical trial.

Furthermore, the safety data was also comparable with grade 3 or higher cytokine release syndrome occurring in 7% and 16% of patients, respectively. Severe neurotoxicity was similar at 39% and 33%, respectively. The toxicity data is also very similar to the ZUMA1 study. Taken together, these studies are encouraging for CAR T-cell use in Canada, but caution should be noted given their very short follow-up time. Continuing the theme of real-world evidence, abstract 96 looked at the safety of Axi-Cel in elderly patients, defined as ≥65 years. Investigators found that the response rate, survival, and toxicity rates were all very similar to the figures listed above, but it should be noted that of 72 patients included (67 evaluated), only 20 met the definition of elderly.

In more traditional treatment methods, data regarding therapies for mantle cell lymphoma (MCL) and other indolent NHLs was presented today. Induction therapy for transplant-eligible patients with MCL remains contentious. The inclusion of cytarabine appears to be the most important aspect regardless of exact regimen. Two separate, phase II, pooled study results looked at 3 cycles of rituximab and bendamustine combined with 3 cycles of rituximab and cytarabine prior to transplant (abstract 145). It is worth noting that cytarabine was given at 3 g/m2 twice daily on days 1 and 2. The first study gave the two combinations sequentially while the second study alternated. ORR was 98% while the 3-year PFS was 88% (median follow-up was 32 months). Typical factors negatively impacted outcomes such as higher risk international prognostic risk score and blastoid variant. These robust outcomes bring up the question as to whether or not transplant is still necessary, but obviously that was a question that could not be answered in this study. Ultimately, this combination is interesting and worth adding to the list of possible induction regimens for patients with MCL. It may be worth it to directly compare induction regimens to help separate whether there is a difference or not between them. For relapsed MCL patients, updated data on zanubrutinib (BGB-3111) was presented from their original phase II study (abstract 148). In brief, zanubrutinib was given to 85 relapsed or refractory patients with MCL at 160 mg twice daily until progression. ORR was 83.5% and 6-month PFS was 82%. Patient characteristics appear most similar to the LY-004 trial of acalabrutinib, another Bruton tyrosine kinase (BTK) inhibitor. With ibrutinib, acalabrutinib, and zanubrutinib, the anti-BTK market is getting quite dense. Cross-trial comparison would suggest that efficacy looks comparable between the drugs, but side-effect profiles are slightly different. It’s likely that the toxicity profile may dictate which patients benefit best from one particular BTK inhibitor.

Perhaps more interestingly, a retrospective study of 59 multiply relapsed patients with NHL were studied due to their prior treatment with a checkpoint inhibitor. Investigators were curious whether they may have improved outcomes based on a separate study in classical Hodgkin lymphoma patients that found Hodgkin patients were re-sensitized to chemotherapy following relapse after checkpoint blockade. Conversely though, checkpoint inhibitors by themselves have been quite disappointing in relapsed NHL. In this current study (abstract 93), ORR to post­­–checkpoint inhibitor therapy was 51% with a median PFS of 6.3 months. Even more surprising was that median overall survival (OS) was 25.6 months. The majority of patients were treated with combination chemotherapy while the others were divided between clinical trial options, radiation, and other novel therapies. No one particular regimen was clearly superior to the others in this retrospective study. As a retrospective, no insight into mechanism was demonstrated, but perhaps this data may inform how checkpoint inhibitors may still have an impact on patients with NHL. As a few quick hitting highlights to finish, the poster session saw Canada’s Dr. Laurie Sehn give updated results of polatuzumab vedotin with bendamustine and rituximab/obinutuzumab, with continued OS benefit (abstract 1683). Lastly, long-term updated data from SAKK35 (abstract 1601) failed to find any survival benefit from long (5-year) maintenance over the typical 2-year regimen.