Down syndrome (DS) is associated with an estimated 20-fold increase in the risk of developing B-cell acute lymphoblastic leukemia (B-ALL), and research findings have shown increased rates of relapse, treatment-related toxicity, and treatment-related death in this patient population (DS-ALL).¹ Several studies sought to elucidate these outcomes as well as potential treatment strategies that may be safer and more effective in patients with DS-ALL.

In a study published in the Journal of Clinical Oncology (JCO), researchers with the Children’s Oncology Group examined data on B-ALL patients ages 1-30 years with DS (n=743) and without DS (n=20,067) who participated in 4 Children’s Oncology Group trials between 2003 and 2019.² The DS group represented the largest cohort of patients with DS and newly diagnosed B-ALL to date.

According to the results, a greater number of patients with DS showed minimal residual disease (MRD) ≥0.01% at the end of induction (EOI) therapy (30.8% vs 21.5%; P <.001) compared to patients without DS. This difference persisted at the end of consolidation (EOC) in National Cancer Institute (NCI) high-risk participants (34.0% vs 11.7%; P <.0001).

Patients with DS demonstrated worse 5-year event-free survival (EFS; 79.2% ± 1.6% vs 87.5% ± 0.3%; P <.0001) and overall survival (OS; 86.8% ± 1.4% vs 93.6% ± 0.2%; P <.0001) compared to patients without DS in the overall participant sample and in NCI standard-risk and high-risk subgroups.

Factors associated with worse EFS included “age >10 years, white blood count >50 × 10³/μL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression,” as described in the paper. In NCI high-risk patients with DS, the poorest EFS and OS were observed in CRLF2-high cases.²

In addition, patients with DS showed higher 5-year risk of relapse (11.5% ± 1.2% vs 9.1% ± 0.2%; P =.0008), death in remission (4.9% ± 0.8% vs 1.7% ± 0.1%; P <.0001), and induction death (3.4% vs 0.8%; P <.0001) compared to patients without DS.

Patients with DS experienced higher rates of mucositis, infections, and hyperglycemia compared to patients without DS, and seizures were more common among patients with DS in high-risk trials (4.1% vs 1.8%; P =.005).

“The increased rate of relapse is likely multifactorial and due to DS-ALL cases less often having favorable cytogenetics, which responds better to treatment; patients with DS-ALL having more complications which require dose reductions, delays, and omission of chemotherapy elements; and possibly other unidentified factors,” explained lead author Karen Rabin, MD, PhD, professor of pediatrics in the division of hematology-oncology at Baylor College of Medicine and director of the Leukemia Program at Texas Children’s Cancer Center in Houston.^2,3

“The increased risk of treatment-related mortality is primarily due to increased fatal infections, presumably due to differences in the immune system in children with DS, which compromise their ability to effectively fight infections during chemotherapy,” she said.

The study by Dr Rabin and colleagues also noted that the risk of relapse in patients with DS-ALL, although still significantly higher compared to the risk of relapse in patients without DS, has improved compared to earlier eras.² “Patients with DS and B-ALL have likely benefited from the same factors that have led to improved cure rates in patients with ALL without DS in more recent times — more intensive chemotherapy regimens and improved supportive care,” she told Hematology Advisor.

Dr Rabin described additional measures needed to further improve outcomes in patients with DS and B-ALL. “Ideally, we will have improved treatment regimens that are highly effective without less toxicity; improved supportive care to prevent life-threatening infectious complications; and improved ability to predict who is at highest risk of relapse and treatment-related mortality in order to tailor each patient’s therapy and supportive care measures according to their level of risk.”⁴

In another study published in 2023 in Blood, Dr Rabin and colleagues found that a modified treatment strategy achieved an induction death rate <10% in high-risk B-ALL patients with DS.¹

The regimen consisted of a 3-drug induction, with slow early responders receiving a single dose of anthracycline (daunorubicin 50 mg/m²) followed by interim maintenance-1 consisting of 4 intravenous courses of 2,000 mg/m² methotrexate rather than 5000 mg/m ², and with leucovorin rescue beginning at hour 30 and advancing to hour 36 if tolerated, rather than at hour 42. “Maintenance modifications included administration of vincristine/steroid pulses every 12 instead of every 4 weeks, and equal duration of therapy for boys and girls,” the study authors explained in their report.¹

However, persistent disparities in EOI and EOC MRD levels and 5-year EFS and OS were observed in DS patients compared to patients without DS. “Innovative strategies utilizing targeted therapies and immunotherapy are needed to further improve outcomes” for these individuals, the authors wrote.¹

Current research is focused on the development of novel, less toxic treatment regimens that incorporate immunotherapies such as blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cells such as tisagenlecleucel, Dr Rabin noted.

“Prospective randomized trials of emerging new treatment strategies with the potential to reduce both TRM and relapse rate are required,” as stated in the JCO study by Rabin and colleagues.

In a review published in Transplantation and Cellular Therapy, Winestone and colleagues wrote that the poor post-relapse outcomes and increased toxicity associated with standard B-ALL treatment in patients with DS “make CAR-T therapy a very attractive alternative therapy for this special population.”³

While individuals with DS are typically excluded from clinical trials investigating novel ALL therapies, a study published in 2022 examined data from 16 patients with DS-ALL (ages 5-22 years) from 3 trials and found that tisagenlecleucel led to high rates of remission, promising long-term outcomes, and manageable side effects, similar to outcomes observed in patients without DS.⁵ “Therefore, CD19 CAR-T therapy should be strongly considered for this group,” according to Winestone and colleagues.³

References

1. Rodriguez V, Devidas M, Chen Z, et al. Patients with down syndrome and high-risk B-acute lymphoblastic leukemia demonstrate improved outcomes on a modified chemotherapy regimen: a report from Children’s Oncology Group Study AALL1131. Blood. 2023;142(1):824. doi:10.1182/blood-2023-185368
2. Rabin KR, Devidas M, Chen Z, et al. Outcomes in children, adolescents, and young adults with down syndrome and ALL: a report from the Children’s Oncology Group. J Clin Oncol. Published online October 27, 2023. doi:10.1200/JCO.23.00389
3. Winestone LE, Bhojwani D, Ghorashian S, et al. INSPIRED Symposium Part 4A: access to CAR T cell therapy in unique populations with B cell acute lymphoblastic leukemia. Transplant Cell Ther. Published online October 10, 2023. doi:10.1016/j.jtct.2023.10.005
4. Peroni E, Gottardi M, D’Antona L, Randi ML, Rosato A, Coltro G. Hematologic neoplasms associated with down syndrome: cellular and molecular heterogeneity of the diseases. Int J Mol Sci. 2023;24(20):15325. doi:10.3390/ijms242015325
5. Laetsch TW, Maude SL, Balduzzi A, et al. Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2022;36(6):1508-1515. doi:10.1038/s41375-022-01550-z