Are these curtains for the chemo?

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

Results with new therapies – including antibody-drug conjugates and chimeric antigen receptor (CAR) T cell therapies – as well as tyrosine kinase inhibitors have led one expert to question whether it is time for a “curtain call for conventional chemotherapy” in older adults with ALL.

Although a more appropriate question may be, “Are these curtains for chemotherapy?” The question was asked by Marlise Luskin, MD, MSCE, of the Dana-Farber Cancer Institute in Boston, Massachusetts, who was speaking in an educational session here at the 2021 annual meeting of the American Society of Hematology.

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

“Today, in 2021, as a 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, with about half of these being in patients over the age of about 50 or 60,” she noted.

“Even adults who are fit enough for treatment with intensive chemotherapy regimens have lower results than [those for] their pediatric counterparts, and although young adults have seen their results improve when treated on pediatric-inspired regimens, most adults in 2021 are not cured of their disease, ”she said. commented.

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

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

There is also 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 people with Ph-ALL has demonstrated high response rates and low early mortality, although longer-term efficacy and safety data are available. still needed, Luskin commented.

Also in this elderly population with Ph-positive ALL (Ph + ALL), tyrosine kinase inhibitors (TKIs) have revolutionized care and made it possible to reduce or omit conventional chemotherapy, she said.

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

“Historically this subtype (Ph + ALL) has had an unfavorable prognosis, but in the era of TKI outcomes have improved for patients of all ages, and is now considered in the older population to be equivalent otherwise better than patients with Ph-negative ALL, because TKIs alone in combination with steroids can induce remissions in a significant number of patients and allowed the reduction or omission of conventional chemotherapy at the start of treatment, this which has been particularly beneficial for older patients, ”said Luskin.

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

However, treatment options for patients with T-cell-induced ALL are still lacking, Luskin pointed out.

Achieve MRD negativity

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

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

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

“When we talk about treatment decisions based on MRD, we usually think of the first line of treatment, and in this situation measuring the MRD shows us the individual response to standard first-line chemotherapy regimens. However, MRD is also gaining importance as an indication. the effectiveness of the new compounds, ”she said.

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

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

The German multicenter ALL group (GMALL) defines complete molecular remissions (CR) as MRD negativity with a sensitivity of 10-4 or less, and molecular failure as MRD positivity as anything above that threshold of 10-4 . There are also categories of molecular intermediates: positive MRD less than 10-4, non-evaluable MRD and molecular relapse after previous molecular CR.

Factors of MRD that can affect treatment decisions include the level of MRD and when it occurs, as well as the subtype and prognostic indications of the various characteristics. Higher degrees of MRM, as well as the persistence of MRM later in treatment, are both generally prognostic for worse outcomes, she noted.

Treatment options based on the results of MRD for patients with poor initial responses include intensification of chemotherapy and possible allogeneic stem cell transplantation, as well as the use of new target approaches to eradicate MRD.

CAR T or new therapies?

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

“There are several things to consider when choosing between CAR T cell therapy and other potential therapies,” Frey said. “The first, of course, is whether this is 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 pediatrics and adults. “

“The question then becomes whether it is clinically feasible? Is there a clinical and logistical window for pheresis, and is there a realistic transition 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 pretreated patients, and the remissions it induces are rapid. Long-lasting remissions are possible, although they vary by product, she said.

“When considering the potential benefit of CAR T cells over other products, it is essential to take into account the patient’s transplant history: are they relapsing after an allogeneic transplant? Frey said.

Toxicities with CAR T cells – including cytokine release syndrome (CRS) and associated immune effector cells neurotoxicity (ICANS) – vary depending on CAR T concept used, disease burden, patient age and co-morbidities. These considerations will be taken into account when choosing between CAR T therapy and other initial treatment options, such as blinatumomab and inotuzumab, Frey said.

CAR T therapy can serve as a successful gateway to an allogeneic transplant, but CAR T on its own is able to induce lasting remissions, so the question becomes “to transition or not?” Frey said more data is needed to conclusively answer this question.

What about the transplant?

During the question-and-answer session, Bryan D. Huber, MD, of Intermountain Healthcare in Salt Lake City, Utah, asked if an initial transplant should be considered in older, fit adults with Ph + ALL.

“I think that’s a great question with no easy answer,” Luskin replied. “As I approach older people with Ph + ALL, what encourages me is that many patients with the ability for TKIs and the incorporation of new agents as well as the ability to sequence TKIs often get deep and very long remissions. Although cure may not be possible in these situations, these remissions can last for years, and for patients who may have high toxicity or who may not be doing well with the transplant, the transplant may not be the right option. “

She also recognized that there is a range of fitness levels in the elderly, “and I think very carefully about whether a patient is likely to do well with a transplant before referring him or her, given that he now has very good treatment options “.

Gökbuget disclosed speaker fees, travel assistance, and advisory board participations for several companies. Frey disclosed Novartis research funding and advice to others. Luskin and Huber did not disclose any relevant financial relationship.

American Society of Hematology 63rd Annual Meeting and Exhibition: Education Session. Presented on December 11, 2021.

Award-winning medical journalist Neil Osterweil is a long-time and frequent contributor to Medscape.

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