Understanding the Need for New Treatment Strategies for Infants with Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. Currently, the 5-year overall survival rate associated with the disease among children is >90%.¹ However, infants (aged <1 year) have not experienced the same survival rates as older children, with the most current documented survival rate among this subgroup being only 40% to 50%.²

This article will discuss some of the characteristics that contribute to poor prognosis in infants with ALL, the results of clinical trials evaluating newer therapies to treat the disease, and what the future holds in terms of novel strategies.

What Leads to Poor Prognosis in Infants with ALL?

“Infant ALL” is characterized by a high rate of genetic rearrangements involving the mixed lineage leukemia (MLL) gene, which accounts for approximately 80% of all cases.² MLL rearrangement (MLL-r) typically distinguishes infant ALL from other types of childhood leukemia. The MLL-r worsens the prognosis of infants compared with that of infants with the MLL-germline (MLL-G) mutation or those without MLL-r.

In addition, the incidence of hepatosplenomegaly and central nervous system involvement is higher in infants with ALL than in older children with the disease.³ Similarly to childhood ALL, age and white blood cell count at presentation also affect prognosis in infants with ALL—younger age and a high white blood cell count are associated with poor prognosis. As with childhood ALL, early relapse (within the first year) also contributes to poorer outcomes in infants with ALL.³

Treatment Strategies for Infants with ALL

Because of patient age and genetic MLL-r, treatment for infant ALL has been modified to involve more intensive treatments, fewer intrathecal treatments, and less steroids than childhood ALL protocols. Researchers are also investigating the use of genetic targeted therapies because these treatments target genetic coding specifically for the oncologic process and have the potential to cause fewer side effects compared with traditional chemotherapies.

The novel agent, lestaurtinib, was utilized in the treatment of infants with ALL in the Children’s Oncology Group (COG) clinical trial AALL0631 (closed June 30, 2014, because of accrual). This strategy focused on the inhibition of positive FMS-like tyrosine kinase 3 plasma activity that has also been detected in some patients with acute myeloid leukemia (AML).^4,5 The overall 3-year event-free survival rate for intermediate- and high-risk patients in this trial was 37%. The 3-year event-free survival rate for high-risk patients who did not receive lestaurtinib was 0% versus 20% for those who did. Patients who did not have MLL-r ALL had a 3-year event-free survival rate of 87%. These results show that infants with ALL with MLL-r continued to have poor outcomes, even with the use of a newer therapy.

Before AALL0631, the Pediatric Oncology Group (POG) conducted the P9407 trial from 2001 to 2006.^1,6 The purpose of this trial was to compare the outcomes of using 2 courses of high-dose methotrexate followed by 1 cyclophosphamide/etoposide course during induction and later in consolidation in patients with MLL-r or MLL-G ALL. Dexamethasone was also changed to the less immunosuppressive prednisolone in this trial cohort.⁶ Toxicity was monitored carefully because of the past effects of cranial radiation and continuous infusions of anthracyclines on infants. Unfortunately, the 5-year event-free survival rate was unchanged (42.3%).

The Dutch Childhood Oncology Group trial, Interfant-99, which included cancer research groups from the Netherlands, Germany, Italy, New Zealand, France, and the United Kingdom, was conducted from 1999 to 2005.^1,7 Infants with ALL were given a hybrid regimen based on the standard protocol for ALL, with some elements designed for treatment of AML, which was a novel approach. Uniquely, doses were adjusted based on the age of the infant at the start of each cycle. Induction consisted of vincristine, daunorubicin, dexamethasone, low-dose cytarabine, and L-asparaginase. Later cycles included more intensified chemotherapy with high-dose methotrexate and cytarabine. However, as in P9407, the 5-year event-free survival rate remained low (46.1%).^1,7

The Interfant-06 trial, which is currently recruiting, is randomizing postinduction medium- or high-risk infants with MLL-r ALL to receive standard treatment or an AML-styled intensified treatment, including daily intravenous low-dose cytarabine, daunorubicin or mitoxantrone, and etoposide.¹ Results are pending because this study is still open outside of the United States.

The use of hematopoietic stem-cell transplantation (HSCT) has also been investigated in infants with ALL. CCG 1953, POG-9407, Interfant-92, and Interfant-99 all offered the option of HSCT to patients with MLL-r in remission, if a suitable donor was available.¹ Although there did not appear to be any additional benefit from HSCT in these trials, further investigation is recommended, and the best time to perform HSCT needs to be clarified.

A New Approach

It is evident that new therapeutic strategies must be implemented to improve overall response rates and reduce treatment-related toxicities in infants with ALL. The new COG trial, AALL15P1, has been designed to include the use of azacitidine before each cycle of chemotherapy.⁸ The chemotherapy arms in this study are based on the standard high-risk arms from Interfant-06.9 Toxicity, tolerability, and long-term outcomes will be monitored.

DNA methyltransferase inhibitors, including azacitidine, have been shown to unsilence genes on MLL-r cells, making them more susceptible to chemotherapy.^10,11 This is a different mechanism of action than lestaurtinib, which works with the FMS-like tyrosine kinase 3 genetic marker. Previous studies with DNA methyltransferase inhibitors in infant ALL have shown time-dependent cytotoxicity to chemotherapy and that some demethylation is enough to cause MLL-r ALL cells to undergo apoptosis.^10,11 AALL15P1 will be a pilot clinical trial to determine the safety of azacitidine with the selected chemotherapy. Only patients aged <12 months will be enrolled, and they will receive 5 daily infusions of azacitidine before each block of chemotherapy, which will end before the start of maintenance therapy.

Infants who have ALL with MLL-r are a challenging patient group to treat, and survival rates remain very low, as illustrated by the results of the previously mentioned clinical trials. “Infant ALL” is very different from childhood ALL with regard to genetics and response to chemotherapies; standard ALL therapy is not sufficient, and more intensive therapy is needed. The AALL15P1 clinical trial includes the novel use of an older agent to help increase the sensitivity of the MLL-r ALL to chemotherapy. The hope is that incorporating this genetically targeted treatment will help to improve outcomes and survival rates for patients with this difficult-to-treat disease.

References

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4. Brown P. Treatment of infant leukemias: challenge and promise. Hematology Am Soc Hematol Educ Program. 2013;2013:596-600.
5. Brown P, Kairalla J, Wang C, et al. Addition of FLT3 inhibitor lestaurtinib to post-induction chemotherapy does not improve outcomes in MLL-rearranged infant acute lymphoblastic leukemia (ALL): AALL0631, a Children’s Oncology Group study. Pediatr Blood Cancer. 2016;63:S7.
6. Dreyer ZE, Hilden JM, Jones TL, et al. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer. 2015;62:419-426.
7. Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370:240-250.
8. ClinicalTrials.gov. Azacitidine and combination chemotherapy in treating infants with acute lymphoblastic leukemia and KMT2A gene rearrangement. https://clinicaltrials.gov/ct2/show/NCT02828358. Accessed December 18, 2017.
9. ClinicalTrials.gov. Different therapies in treating infants with newly diagnosed acute leukemia (Interfant06). https://clinicaltrials.gov/ct2/history/NCT00550992?V_19=View#StudyPageTop. Accessed April 2, 2018.
10. Stumpel DJ, Schneider P, van Roon EH, et al. Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options. Blood. 2009;114:5490-5498.
11. Schafer E, Irizarry R, Negi S, et al. Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: biology and therapeutic targeting. Blood. 2010; 115:4798-4809.