Attaining MRD Among Next Steps in the ALL Paradigm

Nelson Jen An Chao, MD

Therapeutic agents in acute lymphoblastic leukemia (ALL), the most impactful of which may be the CAR T-cell therapies, have shown curative potential as well as underscored the importance of achieving minimal residual disease (MRD) negativity, said Nelson Jen An Chao, MD.

Although MRD continues to be investigated, the importance of achieving MRD negativity was clearly demonstrated in the phase II ELIANA trial. Results from the preliminary analysis of the study served as the basis for the August 2017 FDA approval of tisagenlecleucel (Kymriah) for the treatment of pediatric and adult patients ≤25 years with B-cell precursor ALL that was refractory or in second or later relapse. Since then, the FDA has expanded its indication for use in adult patients with relapsed/refractory large B-cell lymphoma after exposure to ≥2 lines of systemic therapy.

At the 2018 ASH Annual Meeting, updated findings indicated similar rates of relapse-free survival (RFS) and overall survival (OS) with the CD19-targeted CAR T-cell therapy in pediatric and adult patients with relapsed/refractory ALL. Specifically, the rates of RFS was 66% at 12 and 18 months. Additionally, the rates of OS were 76% and 70% at 12 and 18 months, respectively.

Notably, 82% of patients experienced a complete remission (CR) or CR with incomplete blood count recovery at 3 months. Nearly all of these patients (98%) achieved MRD negativity in the bone marrow.

Next-generation sequencing analysis confirmed that both the duration of response and OS were prolonged in patients who achieved MRD negativity. Further, the likelihood of achieving a durable response was lower in patients who were MRD-positive versus MRD-negative, regardless of having achieved a CR. These findings paralleled projections of OS, in which the probability of OS was 0.9 in the MRD-negative group and 0.35 in the MRD-positive group.

“The greatest use for MRD is to try to understand what to do next for the patient,” said Chao. “If patients are in an MRD-[negative] state, most of us would probably stop therapy, whereas if the patient is not in an MRD-[negative] state, they would go onto receive either more therapy or undergo stem cell transplant.”

However, the extended follow-up did reveal an array of toxicities to be aware of, including neurological events and cytokine release syndrome (CRS), which occurred in 39% and 77% of the overall population, respectively. According to grade, 22% of patients experienced a grade 3 CRS event and 27% experienced a grade 4 CRS event.

The second CAR T-cell therapy to receive regulatory approval was axicabtagene ciloleucel (axi-cel; Yescarta), which is indicated for the treatment of adults with relapsed/refractory non-Hodgkin lymphoma.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Chao, professor of medicine, Donald D. and Elizabeth G. Cooke Cancer Research Professor, chief, Division of Cell Therapy in the Department of Medicine, Duke Cancer Institute, discussed current understandings of MRD and the therapies that have helped promulgate its utility in ALL.

OncLive^®: What is the role of MRD in ALL and how do you define MRD?

Chao: [In my presentation], I spoke about MRD, what it means, what we measure, as well as the potential implications of having residual disease or not. The key takeaway that I would like people to understand is that there are multiple ways of measuring MRD. Currently, most of us use flow cytometry, although there is polymerase chain reaction testing as well.

How do the assays differ, and how do you determine which one to order?

It really differs in terms of sensitivity, cost, expertise, and primarily accepted standards, which can vary between institution.

What types of therapeutic developments have resulted in higher rates of MRD negativity?

That is a really good question. We do not know that, but it is something we are trying to understand. Now, MRD is a “yes or no” question; it is something that we assess for at the end of therapy. The real question is, “What do we know about getting an MRD-positive patient to a MRD-negative patient? What does that mean?” Those studies are ongoing.

Have any drugs thus far have helped patients get to an MRD-negative state?

Drugs such as blinatumomab (Blincyto) and brentuximab vedotin (Adcetris] have been used and seem to be working.

Could you expand on some of the data that we have seen with some of these drugs?

These drugs are quite efficacious. However, with regard to safety data, these are chemotherapies, therefore, they are toxic drugs. There are concerns in terms of toxicities, but in general they have been working pretty well in terms of pushing patients into MRD negativity.

What has the impact of CAR T-cell therapy for patients 25 years of age and younger been? How are the toxicities managed?

In ALL, CAR T-cell therapy is curative, which has been pretty dramatic in terms of impact; however, it is toxic. The major toxicities are CRS and neurotoxicity. Cytokine release can become quite severe. It does require hospitalization and stay in the intensive care unit to manage the symptoms.

Could you shed light on any ongoing research in ALL?

CAR T-cell therapy is one area. There are two interesting pieces in both the pediatric space and the adult space. In the pediatric space, it is interesting to see dose de-escalation [trials] to see whether we can still get the same impact. In adults, we are looking at using pediatric regimens to see whether we can improve outcomes, which seems to be the case. Then, there are these trials of pushing patients who are MRD-positive into an MRD-negative state.

Is the de-escalation approach being explored with CAR T-cell therapy as well?

No, we are just trying to use less of the current drugs, especially if patients achieve MRD negativity.

What key challenges remain in the field?

The key challenge is the relapsed/refractory setting. CAR T-cell therapy has a spot there, but obviously not everybody receives CAR T-cell therapy. It is pretty toxic, so there is a lot of room for improvement in that patient population.

Grupp SA, Maude SL, Rives S, et al. Updated analysis of the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia. Blood. 2018;132(suppl 1):895. doi: 10.1182/blood-2018-99-112599.