HSCT Remains Standard in Childhood ALL, Despite CAR T-Cells

Liam Davenport

March 26, 2019

FRANKFURT, Germany — Hematopoietic stem cell transplantation (HSCT) should still be considered the standard of care for children with acute lymphoblastic leukemia (ALL) as, despite promising results, chimeric antigen receptor (CAR) T-cell therapies currently remain unproven, says a leading expert.

Peter Bader, MD, professor of pediatrics at Johann Wolfgang Goethe University, Frankfurt, Germany, explained that overall survival with stem cell transplants in children with ALL has been increasing, reaching as high as 80% at 4 years in specialized centers.

However, results can be less impressive with subsequent transplants, with overall survival dropping to around 30%, he noted.

This has led to interest in alternative treatments, such as CAR T-cells.

Indeed, trials with tisagenlecleucel (Kymriah, Novartis) in children with relapsed/refractory B precursor ALL have shown impressive results, leading to its approval by the US Food and Drug Administration (FDA) in 2017.

Bader nevertheless underlined that allogeneic HSCT "is the standard of care for high-risk patients with complete remission one, two [years] and beyond, because this is the benchmark."

He said that CAR T-cells "still have to prove whether they can outperform that [treatment], because the survival of our patients is really our utmost priority, of course."

Bader added that, while the data on CAR T-cells is increasing and there is "an abundance" of data from his institute, the number of patients treated overall remains small.

Bader was speaking here at the European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019.

Lola Manterola, president and founder of the CRIS Cancer Foundation, and treasurer of the EBMT Patient, Family and Donor Committee, co-chaired the session.

She told Medscape Medical News that HSCT has been "proven", with predictable results, and that the "optimal" transplant is with a matched donor.

"But CAR T-cells are the future and are, at the moment, a good alternative when the transplantation has not worked," she said.

Manterola nevertheless cautioned that "we still need to predict which patients are able to receive CAR-T cells," noting that this is the subject of ongoing research.

"For the time being, we should keep asking donors to donate to have more matches for bone marrow transplants, but we should keep an eye on this new therapy for the patients who are relapsing and keep investing in research to give the physicians the possibility to give more alternatives and use CAR T-cells in the future," she said.

Manterola added that "it is interesting for me as a patient" to know that CAR T-cells have strong adverse effects, "because sometimes you believe that immunotherapy does not have as many adverse effects." She overcame multiple myeloma and cofounded CRIS Cancer Foundation with her husband, Diego Megia.

She therefore said that, for now, "we should just try to focus on the best treatment for patients."

Complex Procedure

In his presentation, Bader highlighted that, while stem cell transplantation has become an "excellent treatment option" for high risk patients, it nevertheless remains "complex" and potentially dangerous.

Consequently, patients need to be selected carefully.

To examine the performance of HSCT in high-risk ALL, Bader looked at results from the ALL-SCT-BFM-2003 study, which was published in 2015 in the Journal of Clinical Oncology.

For this, 411 children underwent transplants from either a matched sibling donor (MSD; n = 105) or a matched unrelated donor (MUD; n = 306).

Four-year event-free survival was similar between the two groups, at 71% in MSD patients and 67% in MUD patients (P =.405).

Moreover, the 4-year relapse incidence was again similar, at 24% in patients given an MSD transplant and 22% of those in the MUD group (P = .732).

There was, however, a significantly higher incidence of non-relapse mortality in the MUD group, at 10% vs 3% with MSD transplantation (P = .017).

Data from Frankfurt 

Next, Bader presented data from his own institute in Frankfurt on 162 acute myeloid leukemia (AML) and ALL patients given allogeneic HSCT between 2005 and 2016.

Their results, published last year, showed that, when stratifying patients by donor source, there were no significant differences in 4-year overall survival (P = .45), event-free survival (P = .61), cumulative relapse incidence (P = .11), or non-relapse mortality (P = .19).

There nevertheless remained notable differences between MSD and MUD patients in terms of cumulative relapse incidence, at 38% and 17%, respectively, and non-relapse mortality, at 3% and 15%, respectively.

In patients with ALL specifically, Bader noted that, as in the ALL-SCT-BFM-2003 study, the difference in non-relapse mortality between MSD and MUD patients became significant (P = .05).

The higher risk of relapse with MSD vs MUD transplants was also significant in patients with ALL (P = .02) in this study.

Despite this, Bader showed that he and his colleagues have been able to improve survival following HSCT in patients with acute leukemia, from 68% in 2005–2008 to 80% in 2012–2016.

This has been driven largely by a fall in the rate of 4-year non-relapse mortality from 20% to 7% over the same period.

Among patients with ALL, the decrease in non-relapse mortality has been significant, from 19% in 2005–2008 to 4% in 2012–2016, at a hazard ratio of 0.20 (P = .04).

But What Next?

The question then becomes what to do once a patient has experienced a relapse.

Bader pointed to data showing that a second HSCT in patients with ALL was associated with a 5-year leukemia-free survival rate of 31%, and an overall survival of 33%.

This is reflected in a 5-year cumulative relapse incidence of 47% and a non-relapse mortality rate of 22%.

Bader said that these results underline the "challenges" of treating patients who have relapsed.

"That's why we have to develop new treatments," he continued, "and these could be, for example, CAR T-cell therapy."

There has been a great deal of media interest in CAR T-cell therapy for childhood leukemia, Bader said.

This was particularly the case after Grupp and colleagues from Philadelphia published their results in two patients with ALL in 2013, showing complete remission with CD19-targeted CAR T-cells.

This was followed by the launch of the ELIANA single arm, open-label, phase 2 trial by Novartis to examine the effectiveness of this therapy, later named tisagenlecleucel, in relapsed and refractory B-cell ALL.

For this trial, patients were required to be positive for CD19 expression, and to be in good clinical condition, with disease control maintained for 2 to 4 months.

Bader explained that the maintenance of disease control is required because it currently takes around 3 months for the therapy to be prepared, partly due to having to send the blood cells collected from the patient to the United States for processing. 

In spite of these limitations, the ELIANA trial was able to show that tisagenlecleucel was able to achieve remission in 61 (81%) of 75 children with relapsed and refractory B-cell ALL at 3 months.

Event-free survival at 12 months was 50%, while overall survival was 76%.

Bader pointed out, however, that 73% of patients experienced grade 3/4 adverse events suspected of being related to tisagenlecleucel, and 77% had cytokine release syndrome of any grade.

Ongoing Interest in CAR T-Cell Therapy 

These results have driven ongoing interest in CAR T-cell therapy.

Bader said that there are four ongoing clinical trials with CD19-directed therapies, involving a total of 183 patients with a range of clinical profiles.

These have, thus far, shown good event-free and overall survival rates, comparable to those seen in ELIANA.

However, they have also underlined that there are a number of variables that can affect outcomes with CAR T-cell therapy.

Some are patient-related, such as age and prior therapy, while the expanded T cells, particularly if poorly expanded, can express genes that are associated with glycolysis, exhaustion, and apoptosis; in addition, there is the possibility of 'antigen escape' of the leukemia cells.

In the post-presentation discussion, Bader expanded on some of the issues that can occur with CAR T-cell therapy, noting that, although it does not occur often, the leukemia cells can change between leukapheresis and modified T-cell infusion.

He explained that the leukemia cells can "release" the CD19 into the plasma and become "inert." Consequently, they can no longer be attacked by the CAR T-cells.

Bader said this is, unfortunately, a relatively common problem, accounting for 30% of relapses following CAR T-cell therapy.

Looking at when to use CAR T-cells clinically for the treatment of patients with B-cell ALL, Bader pointed the audience to the consensus statement from the EBMT and American Society for Blood and Marrow Transplantation, published in 2018.

This consensus statement was produced to serve as "an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved."

When the FDA approved tisagenlecleucel for this population, the indication was for use in patients ages 25 years or younger who have relapsed/refractory disease, and this was the starting point for the consensus statement, Bader commented.

Bader emphasized that HCST is, in general, recommended for the ALL patient who has experienced failure of primary induction therapy.

He continued: "If I have a T-cell leukemia, so a subgroup basically who can't cope with chemotherapy very well, and it leads to persistent minimal residual disease, then we have an indication for allogeneic transplantation."

For patients in the hypodiploid subgroup, expert opinion says that HSCT is recommended.

However, Bader said that it can be "difficult" for these patients to have a transplantation, "and here we can recommend CAR-T cells."

Patients with a B phenotype who "cope quite well with chemotherapy" and express CD19 could undergo either HSCT or CAR T-cell therapy, Bader said.

By the time of the third remission, however, he noted that HSCT is the recommended treatment.

Bader declares research grants from Neovii, Riemser, Medac; advisory board membership for Novartis, Celgene, Amgen, Medac, Servier; speaker's bureau for Miltenyi, Jazz, Riemser, Novartis, Amgen; and patent and royalties with Medac.

European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019: CAR T-cells or transplantation? Pros/Cons. Presented March 24, 2019.

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