Immunotherapy sparks hope for paediatric ALL

Despite a 90-percent cure rate after first treatment for children with acute lymphoblastic leukaemia (ALL), approximately 10–15 percent of patients with paediatric ALL will experience relapse. [Expert Rev Anticancer Ther 2017;17:725-736] A recent webinar on the current landscape of ALL highlighted the potential of immunotherapy for paediatric patients with relapsed or refractory ALL, thus providing hope for this high-risk patient group.

“About 40 percent of childhood ALL relapses occur >6 months after stopping treatment, up to 10 years following diagnosis … Among high-risk relapses (relapses within 6 months from stopping therapy), approximately a third do not get into remission, and about half of patients who are transplanted relapse,” said Professor Vaskar Saha from the University of Manchester, UK and the Tata Translational Cancer Research Centre, Kolkata, West Bengal, India, during a discussion. “Immunotherapy does provide great hope for this group of patients.”

 

Chemotherapy: The downside

The primary treatment for paediatric ALL is conventional chemotherapy (CT). [www.cancer.org/cancer/leukemia-in-children/treating/children-with-all.html, accessed October 6, 2020] The Total studies, which has been running for nearly 6 decades, reflect a favourable overall survival (OS) trend with CT in this setting. [Haematologica 2020;doi:10.3324/haematol.2020.247031]

In Total I–IV (1962–1966), OS rate was low at 21 percent. This continued to improve over time, reaching up to about 94 percent in both the Total XV (2000–2007) and XVI studies (2007–2017). [Haematologica 2020;doi:10.3324/haematol.2020.247031; Nat Rev Clin Oncol 2019;16:227-240] “This was made possible by optimizing the dosing schedule of conventional CT through improved risk stratification and the use of pharmacodynamic and pharmacogenomic data, as well as better supportive care,” said discussant Professor Hiroto Inaba from the Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee, US, who is also the principal investigator of the Total studies.

“This is a great success story [in paediatric ALL],” commented moderator Dr Rajat Bhattacharyya from the Paediatric Haematology Oncology BMT, KK Women’s and Children’s Hospital, Singapore. “[However, despite the significant success with conventional CT,] some children have high-risk features. Hence, they either do not respond to treatment very well or they relapse after treatment; this is the challenge … The cure … stops somewhere, and there lies the issue,” he stressed.

Inaba also raised the issue of tolerance. “As the intensity of CT comes to the limit of tolerance, increasing CT may not necessarily lead to improved survival. [It may] increase toxicities.”

 

Incorporating immunotherapy

“To further improve outcomes, we are exploring prospective comprehensive genetic analysis, combined with MRD monitoring, for more comprehensive risk classification, and if feasible, use molecular targeted therapy, such as TKIs* and immunotherapy (eg, blinatumomab, CAR** T-cell therapy),” said Inaba. TKIs specifically target molecular abnormalities driving cancer progression, whereas immunotherapeutic agents target patients with persistent minimal residual disease (MRD) and/or high-risk genetic features. [Blood 2012;120:5094-5095; Eur J Haematol 2017;98:425-434; Hematology Am Soc Hematol Educ Program 2014;2014:559-564]

The risk of relapse is associated with high MRD (≥1 percent), said Inaba. “But even if end of induction MRD is negative, patients with NCI*** high-risk B-ALL and T-ALL still relapse. [Therefore,] we should consider [immunotherapy for] patients who are MRD-positive at end of induction, or for MRD-negative patients with high risk genetics.”

Saha concurred, “[In] patients who are MRD-positive or have high-risk cytogenetics, even after transplantation, [there is] recurrence. In both categories, there is a role for immunotherapy, perhaps at the end of CT to clear any residual cells.”

Major paediatric leukaemia study groups are now using immunotherapy in the front-line treatment setting of ALL. CAR T-cell therapy is mostly used for very high-risk patients with MRD-persistent disease, while the CD3/CD19 conjugated antibody blinatumomab is used by COG^# and the AIEOP/BFM^## for standard-risk and intermediate-/high-risk ALL, respectively. [Am Soc Clin Oncol Educ Book 2020;doi:10.1200/EDBK_278171]

Regarding adverse events, blinatumomab and CAR T-cell therapy may cause neurotoxicity and cytokine-release syndrome. Additionally, in CAR T-cell therapy, the incidence of hypogammaglobulinaemia – which intensifies patients’ susceptibility to potentially life-threatening infections – may be long-term and even permanent as long as CAR T-cells are present, Inaba pointed out. [Pediatr Blood Cancer 2018; 65:e26914]

 

Blinatumomab

Blinatumomab, a first-in-class bispecific T-cell engager antibody, has shown potential in the management of refractory ALL. [J Clin Oncol 2011;29:2493-2498; J Clin Oncol 2014;32:4134-4140; Clin Adv Hematol Oncol 2012;9:776-777]

In a study on children with intermediate-/high-risk, relapsed ALL, better efficacy outcomes were observed across most endpoints in favour of blinatumomab over CT. Two-year disease-free survival (59 percent vs 41 percent; p=0.05) and OS (79 percent vs 59 percent; p=0.005) were significantly better with blinatumomab vs CT. There were also more blinatumomab recipients who achieved MRD clearance (79 percent vs 21 percent) and progressed to HSCT^### (73 percent vs 45 percent; p<0.001 for both) compared with those who received CT. [Blood 2019;134 (Suppl 2):LBA-1]

Blinatumomab also fared better than CT in terms of safety, as shown by the lower rates of grade ≥3 adverse events during the second post-randomization block (0 percent vs 46 percent [febrile neutropenia], 11 percent vs 61 percent [infection], 2 percent vs 21 percent [sepsis]; p<0.001 for all), as well as the number of toxic deaths (n=0 vs 4; p=0.05). [Blood 2019;134 (Suppl 2):LBA-1]

Inaba also shared interesting findings from a small phase II study evaluating the effect of blinatumomab in adults with MRD-positive ALL, particularly those who did not proceed with HSCT. [Blood 2012;120:5185-5187] ] The study showed that relapse-free survival at 30 months was comparable for patients who had undergone HSCT (n=9), and those who had not (n=11) (65 percent vs 60 percent). “Eleven out of 20 [patients] did not go to transplant, yet 60 percent were alive without transplant after that. [This implies that] blinatumomab may be effective in the earlier stage or lower levels of disease … Blinatumomab used in [low-level MRD] with continued CT [as] front-line maintenance therapy … may cure the patient,” he said.

 

Improving the ALL treatment landscape

“Possible strategies to improve survival of ALL patients include the identification of leukaemia subtypes by prospective analysis and sequencing, the monitoring of MRD, detailed comprehensive risk classification, and the incorporation of targeted therapy and immunotherapy for persistent MRD or high-risk genetic features,” said Inaba.

“Immunotherapy may help achieve better MRD and delay relapses. However, we do need longer follow-ups,” commented Saha. Inaba added that the high cost of immunotherapy is another issue that needs to be taken into account, especially in low-/middle-income patient settings. He expressed hope that immunotherapy and targeted therapy for ALL may soon be available for use globally, including in resource-limited countries.