Novel Agents for Adult ALL: Is it Curtains for Chemo?

Neil Osterweil

December 21, 2021

ATLANTA, Georgia — Chemotherapy has been the mainstay of treatment for adults with acute lymphoblastic leukemia (ALL) for many decades, but new approaches are now muscling in.

The results being achieved with novel therapies — including antibody-drug conjugates and chimeric antigen receptor (CAR) T cell therapies — as well as tyrosine kinase inhibitors have led one expert to ask whether it's time for a "curtain call for conventional chemotherapy" in older adults with ALL.

The question was asked by Marlise Luskin, MD, MSCE, from Dana-Farber Cancer Institute in Boston, Massachusetts, who was speaking at an educational session here at the 2021 American Society of Hematology annual meeting.

The session was focused on how best to use these new approaches to improve the survival of older adults with ALL.

"Today, in 2021, as the result of decades of collaborative research, the vast majority of children in resourced medical centers are cured of ALL," Luskin told the audience.

"However, half of ALL diagnoses occur in adults, approximately half of those being in patients over the age of approximately 50 or 60 years," she noted.

"Even adults fit enough for treatment with intensive chemotherapy protocols have outcomes that are inferior than [those for] their pediatric counterparts, and while young adults have seen improvements in their outcomes as they are treated on pediatric-inspired regimens, most adults in 2021 are not cured of their disease," she commented.

Agents currently approved for the treatment of relapsed/refractory B-ALL include the bi-specific T-cell engager blinatumomab (Blincyto) and the antibody-drug conjugate inotuzumab ozogamicin (Bespona).

In addition, venetoclax (Venclexta), a selective inhibitor of Bcl-2, is currently being investigated for this indication.

There is also the CAR-T cell therapy tisagenlecleucel (Kymriah), although the approved indication specifies that it is for use in r/r ALL in adults under 25 years of age.

Early experience with blinatumomab and inotuzumab in older adults with Ph-ALL has demonstrated high response rates and low early mortality, although data on longer-term efficacy and safety are still needed, Luskin commented.

Also in this population of older adults with Ph-positive ALL (Ph+ALL), tyrosine kinase inhibitors (TKIs) have revolutionized care and allowed for reduction or omission of conventional chemotherapy, she said.

The two approaches are also being tried in combination: a new study presented during the meeting reported good results in older adults with ALL with a combination of blinatumomab with the TKI dasatinib (Sprycel).

"Historically, this subtype (Ph+ALL) has had an adverse prognosis, but in the TKI era outcomes have improved for patients of all ages, and is now considered in the older population equivalent if not better than patients with Ph-negative ALL, because TKIs alone in combination with steroids can induce remissions in a significant number of patients and have allowed the reduction or omission of conventional chemotherapy early in treatment, and this has been particularly beneficial for older patients," Luskin said.

There is still room for improvement of outcomes, however, and it's still unclear which TKIs are best, which combinations of TKIs with other agents offer the best efficacy, and whether there is still a role for chemotherapy in these patients, she added.

However, therapeutic options for patients with ALL of T cell origin are still lacking, Luskin emphasized.

Achieving MRD Negativity

Another leukemia specialist discussed how to help adults with ALL achieve minimal residual disease (MRD) negativity.

Nikola Gökbuget, MD, from Goethe University Hospital in Frankfurt, Germany, began her presentation by discussing the definition of MRD.

A widely accepted definition of MRD is the presence of residual blast cells that are below the detection limit of cytology, which is around 5%.

"When we speak about treatment decisions based on MRD we usually think about the first line of treatment, and in this situation the MRD measurement shows us the individual response to standard first-line chemotherapy protocols. However, MRD also gains increasing importance as an indication of efficacy of new compounds," she said.

The essentials for evaluation of MRD by any method include good primary diagnostic materials and expert laboratory services that adhere to international reference standards, she said.

MRD testing has higher sensitivity for detecting B-precursor ALL in bone marrow than in peripheral blood, although peripheral blood is suitable for follow-up tests in T-cell ALL, she said.

The German multicenter ALL group (GMALL) defines molecular complete remissions (CR) as MRD negativity with a sensitivity of 10-4 or less, and molecular failure as MRD positivity as anything above that 10-4 threshold. There are also categories of molecular intermediate: MRD positive below 10-4, MRD not evaluable, and molecular relapse after prior molecular CR.

MRD factors that can affect treatment decisions include the level of MRD and the timepoint when it occurs, as well as the subtype and the prognostic indications of the various features. Higher degrees of MRD, and also MRD persisting later in treatment, are both generally prognostic of worse outcomes, she noted.

Therapeutic options based on MRD results for patients with initial poor responses include intensification of chemotherapy and possible allogeneic stem cell transplant, and also the use of novel target approaches to eradicating MRD.

CAR T or Novel Therapies?

Noelle V. Frey, MD, MS, from the University of Pennsylvania in Philadelphia, discussed the question of whether to use CAR T cell therapy or one of the novel agents.

"There are several things to consider when deciding between CAR T cell therapy and other potential therapies," Frey said. "The first of course is whether it's a feasible option for your patients. If they live near a tertiary care center, access is now less of a concern given the availability of commercial products for both pediatrics and adults."

"The question then becomes is it clinically feasible? Is there a clinical and logistical window for the pheresis, and is there a realistic bridging plan based on your patient's disease burden and treatment history?" she continued.

CAR T cell therapy is associated with CR rates ranging from 62% to 93% in heavily pre-treated patients, and the remissions it induces are rapid. Durable remissions are possible, although they vary by product, she said.

"When considering the potential benefit of CAR T cells compared to other products, it's critical to consider the patient's transplant history: Are they relapsing after an allogeneic transplant? And if no prior transplant, are they are a candidate if they achieve a CR?" Frey said.

Toxicities with CAR T cells — notably the cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) — vary by the CAR T construct used, disease burden, patient age, and comorbidities. These considerations will factor in to the choice between CAR T therapy and other initial treatment options, such as blinatumomab and inotuzumab, Frey said.

CAR T therapy can serve as a successful bridge to allogeneic transplant, but CAR T alone is capable of inducing durable remissions, so the questions becomes "to bridge or not to bridge?" Frey said more data are needed to answer this question conclusively.

What About Transplant?

In the question-and-answer session, Bryan D. Huber, MD, from Intermountain Healthcare in Salt Lake City, Utah, asked whether upfront transplant should be considered in older, fit adults with Ph+ALL.

"I think that is a great question without an easy answer," Luskin replied. "As I approach older adults with Ph+ALL, what I'm encouraged by is that many patients with the ability of TKIs and with incorporation of novel agents and also the ability to sequence TKIs often achieve deep and very long remissions. Although cure may not be possible in those situations, those remissions can last years, and for patients who may have a high toxicity or may not do well with transplant, transplant may not be the right option."

She also acknowledged that there is a range of fitness among older adults, "and I think very carefully about whether a patient is likely to do well with a transplant before I refer them, given that they have very good treatment options now."

Gökbuget disclosed speaker honoraria, travel support, and advisory board participations for several companies. Frey disclosed research funding from Novartis and consulting for others. Luskin and Huber have disclosed no relevant financial relationships.

63rd American Society of Hematology Annual Meeting & Exposition: Education Session. Presented December 11, 2021.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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