Tanya Siddiqi, MD

In the phase I/II TRANSCEND CLL 004 study (NCT03331198), chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel; JCAR017) led to undetectable minimal residual disease (MRD) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

Patients with CLL or small lymphocytic lymphoma (SLL) who had received 2 previous lines of therapy were given liso-cel at either dose level (DL) 1 of 50 × 106or DL2 of 100 × 106total CAR-positive T cells. Therapy was administered to 15 patients by liso-cel infusion, and 7 patients received bone marrow biopsies. These patients were then monitored for treatment-emergent adverse events, and doses were adjusted based on the emergence of adverse events.

Toxicities were manageable, with the most common toxicities including hypertension and cytopenias. Three patients had grade 3 neurotoxicity, and 1 patient presented with grade 3 cytokine release syndrome (CRS).

Phase II/III data presented during the 15th International Conference on Malignant Lymphoma (ICML) revealed that most patients (88%) had responses to therapy 30 days into the study. There was a high overall response rate (ORR; 83%), which was maintained for 6 months. Sixty-seven percent of patients had undetectable MRD by day 30.1

TRANSCEND CLL 004 showed that CAR T-cell therapy is a promising alternative for patients with CLL who failed previous forms of therapy. The study is ongoing, and the researchers expect to present a follow-up soon.

In an interview withTargeted Oncology, Tanya Siddiqi, MD, an assistant clinical professor in the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope in Duarte, California, explained how novel agents are improving the treatment landscape for CLL with examples from the TRANSCEND CLL 004 trial.

TARGETED ONCOLOGY: How have novel agents changed the treatment landscape for CLL?

Siddiqui:There have been a lot of improvements in CLL therapy within the last few years, starting with ibrutinib (Imbruvica) and so many other agents coming down the pike. The latest advancement has been the venetoclax (Venclexta) plus obinutuzumab (Gazyva) CLL14 clinical trial, showing that the venetoclax arm is better than the chlorambucil plus obinutuzumab arm. [This result] was expected, but it's good to see it in hard data.

This is frontline therapy for patients with comorbidity, but in reality, I have a lot of patients who are younger and interested in finite therapy and even older patients who are interested in finite therapy since they don’t want to be on ibrutinib indefinitely. It's a very good option as an alternative to sticking to 1 year of venetoclax plus obinutuzumab therapy and giving them a break to see what happens overtime. It’s one of the best agents that have come out this year.

TARGETED ONCOLOGY: How do you see acalabrutinib (Calquence) fitting in to this space based on the results of the phase III ASCEND trial?

Siddiqui:It's an excellent option for patients to have if it does come on the market. We presume that acalabrutinib has a slightly better toxicity profile than ibrutinib, which means that it may have fewer hypertension events, bleeding events, and less atrial fibrillation events. All in all, I think it is a very good second option for patients to have if it comes to market.

It clearly showed that things look better with acalabrutinib than they do with idelalisib (Zydelig) and also with bendamustine (Treanda) and rituximab (Rituxan) combinations. Idelalisib isn't used that much in real practice, but this is the first time so far that a study has been reported comparing 2 novel agents to each other. There are a lot of studies ongoing, but nothing has been reported yet. So, for the first time, we are seeing that acalabrutinib is better than idelalisib which is great to know.

TARGETED ONCOLOGY: Are there any other recent developments outside of novel agents in the CLL landscape that you are excited about?

Siddiqui:CAR T-cells are the biggest thing. I presented the results of the Transcend CLL 004 study, which is a study in R/R CLL patients who have all failed ibrutinib previously. More than half have also failed venetoclax previously. This population is pretty poor-acting, so to speak, and are running out of options. Their disease behaves more aggressively. We treated 23 patients with liso-cel, and we found very encouraging results. [There was] a high overall response rate and high CR rate, and even undetectable MRD in the bone marrow and blood was pretty high at 60% to 65%, as early as 30 days after CAR T-cell therapy.

Overall, it's an excellent option. So far, we've seen about 3 or 4 patients beyond the 12-month mark who are still in a complete remission (CR) with detectable CAR T cell in their blood still and also undetectable MRD for CLL which is great. That's probably the most excited.

TARGETED ONCOLOGY: What was the rationale for conducting this study?

Siddiqui:We know that CLL is an incurable disease so far. We've come a long way to improve patient responses compared to just using chemoimmunotherapy. We take patients down to MRD undetectability with novel agents, especially combinations of novel agents. If we try to do fixed-duration novel agent therapy or monotherapy with ibrutinib or venetoclax alone, for example, we can't get patients down to undetectable MRD that reliably. We also can't keep them at undetectable [MRD] reliably.

The thought was, is there a way to actually cure these patients? Can you actually get them undetectable to MRD and never have the CLL come back? One of the ways we thought would be a good idea is to use their own immune system and make CAR T cells out of their T cells and see if they can fight the CD19-positive CLL cells as we did for aggressive lymphoma.

We are seeing the results, at least with the liso-cel monotherapy, is extremely good on this trial. What's more encouraging to me is that others medical centers like the University of Pennsylvania and the Fred Hutchinson Cancer Research Center are doing CLL studies with their CAR T cells, but their monotherapy CAR T cells don't seem to yield results. They're now combining CAR T cells with ibrutinib to improve on those results, and looks like they are going to do that. We thought with liso-cel, the monotherapy results were fabulous, but now we are doing a phase I cohort in which we're adding ibrutinib to the liso-cel to see if we can improve patient response even further. It's exciting.

TARGETED ONCOLOGY: What have been some of the hurdles with integrating CAR T cells into CLL treatment?

Siddiqui:The biggest hurdle is there are so many good, easy oral options for patients so we have to be picky with the patients we take CAR T cells, at least initially until we know that we can cure them. By definition, we can't say that for sure until 5 to 10 years that we have cured them.

I think if patients have aggressive-behaving CLL, it usually comes with the poor-risk features, like deletion 17p and complex cytogenetics. Even the novel agents may not control that type of disease for too long. The argument against CAR T cells being a little more intensive and involved is that those [aggressive] cases might benefit from it a lot, whereas people who are doing good on "watch and wait" may never need treatment and we should leave them alone. For patients with deletion 13q or mutatedIgVH, if they don't need any aggressive treatment like CAR T cells, just leave them on their pills. I think that has been the biggest criticism with CAR T cells for CLL. It's such an easy disease to treat but not for that subset of patients that has aggressive CLL.

I've also seen research presented about complex cytogenetics and their effect in the CLL14 trial, and it seems like the complex genetics have reduced risk and weaker response to the novel agents, especially highly complex cytogenetics. Educationally, that's good for us to be aware of [so that] we can stratify or think about more aggressive treatments for the more bad-acting CLL cases like those with a high number of complex cytogenetics. It was very good to see that data.

TARGETED ONCOLOGY: What did the safety profile look like for liso-cel in the TRANSCEND CLL 004 trial?

Siddiqui:For the TRANSCEND CLL 004 study, we saw easy-to-manage CAR T-cell therapy-related toxicities. The majority of the grade 3 and higher toxicity was cytopenia from chemotherapy. The cytokine release syndrome and neurotoxicity are the main CAR T-cell therapy-related side effects we saw. About 70% of patients had some grade CRS, but only 2 of the 23 patients had grade 3 CRS and no grade 4 or 5 CRS. For neurotoxicity, there were about 39% of patients that had some neurotoxicity, but only 5 patients had grade 3 or 4 neurotoxicity events. There were no grade 5 neurotoxicity events. [Liso-cel] was reasonably well tolerated, or I should say very well-tolerated in this situation.

There were also about 4 tumor lysis syndrome (TLS) events. We didn't see that much TLS in the lymphoma trial, but when you have circulating, abnormal CLL cells in the blood, there's usually more of a TLS risk, like we saw with acute leukemia. We had 4 events of the 23 that were TLS. A couple of them were manageable with allopurinol (Zyloprim) and pills. There were a couple of patients who needed rasburicase and 1 patient who needed dialysis as well.

There were 2 dose-limiting toxicity (DLT) events on level 2. One was severe hypertension, which is unusual because CAR T cells usually cause hypotension, but in this case, it was very severe hypertension at the end of the DLT periods, [which was] around day 28. The other toxicity was some neurotoxicity that latest more than 7 days [and] became a DLT by definition. That patient also had grade 4 TLS, requiring the dialysis, which made is a DLT event.

TARGETED ONCOLOGY: What does the future look like for CAR T-cell therapy in CLL?

Siddiqui:It looks really good in the sense that there is definitely a space for it. I believe we proved that there are some patients who will do extremely well. If you look back to 2011, the first time I read about the CAR T cells was in theNew England Journal of Medicinepaper printed by University of Pennsylvania, and it reported 3 patients with CLL who had just failed every pos

sible line of therapy and they were given CAR T cells. Apparently, 2 of 3 patients are still in a CR 8 years later.

There is certainly something to be said about the potential for a cure in CLL, which is an incurable disease to-date. Secondly, 1 of the things we struggle with on a lot of trials for R/R CLL patients is that if we can get them to undergo through CAR T-cell therapy at earlier stages while they are still fit and haven’t failed say, 5 lines of prior therapies, then, maybe we can have a better shot at trying to cure them.

For instance, in the second-line, if a patient failed a novel agent in the frontline and relapse, their prognosis is already poor. At that point, they can go straight to CAR T cells, and if that does the trick that's great. If it doesn't, you still have backup venetoclax or the alternative novel agents, PI3K delta inhibitors and other things down the line. If we can move it closer to frontline over time, that would be an excellent step for CLL.

Reference:

Siddiqi T, Dorritie KA, Soumerai JD, et al. TRANSCEND CLL 004: Minimal residual disease after lisocabtagene maraleucel in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma.Hematol Oncol. 2019;37(suppl S2):109-110. doi: 10.1002/hon.71_2629.